Sulfonamide compounds

ABSTRACT

Certain sulfonamide compounds are dual CCK1/CCK2 inhibitors useful in the treatment of CCK1/CCK2 mediated diseases.

FIELD OF THE INVENTION

There is provided by the present invention compounds that are dualCCK1/CCK2 receptor modulators. More particularly, there is provided bythe-present invention sulfonamides that are dual CCK1/CCK2 receptorantagonists useful for the treatment of disease states mediated byCCK1/CCK2 receptor activity.

BACKGROUND OF THE INVENTION

This invention relates to cholecystokinin (CCK) receptor ligands. Theinvention also relates to methods for preparing such ligands and tocompounds that are useful intermediates in such methods. The inventionfurther relates to pharmaceutical compositions comprising such ligandsand methods for preparing such pharmaceutical compositions.

The gastrins and cholecystokinins are structurally related neuropeptidesthat exist in gastrointestinal tissue, gastrinomas and, in the case ofthe cholecystokinins, the central nervous system (J. H. Walsh,Gastrointestinal Hormones, L. R. Johnson, ed., Raven Press, New York,1994, p. 1).

The actions of CCK are mediated by two G-protein coupled receptors:CCK-1 (formerly CCK-A) and CCK-2 (formerly CCK-B/gastrin). These CCKreceptors are expressed throughout the gastrointestinal system and indifferent parts of the central nervous system including the cortex, thestriatum, the hypothalamus, the hippocampus, the olfactory bulb, thevagal afferent neurones, in different enteric nerves, and in the genitaltract.

Several forms of gastrin are found including 34-, 17- and 14-amino acidspecies with the minimum active fragment being the C-terminaltetrapeptide (TrpMetAspPhe-NH₂), which is reported in the literature tohave full pharmacological activity (H. J. Tracy and R. A. Gregory,Nature (London), 1964, 204:935-938). Much effort has been devoted to thesynthesis of analogs of this tetrapeptide (and the N-protectedderivative Boc-TrpMetAspPhe-NH2) in an attempt to elucidate therelationship between structure and activity.

Natural cholecystokinin is a 33 amino acid peptide (CCK-33), theC-terminal 5 amino acids of which are identical to those of gastrin.Also found naturally is the C-terminal octapeptide (CCK-8) of CCK-33. Areview of CCK receptors, ligands and the activities thereof may be foundin P. de Tullio et al. (Exp. Opin. Invest. Drugs, 2000, 9(1):129-146).

Gastrin and cholecystokinin are key regulators of gastrointestinalfunction. In addition, cholecystokinin is a neurotransmitter in thebrain. Gastrin is one of the three primary stimulants of gastric acidsecretion. In addition to the acute stimulation of gastric acid, gastrinhas a trophic effect on the gastrointestinal mucosa and is implicated asa trophic hormone of several adenocarcinomas, including pancreatic,colorectal, esophageal and small cell lung.

Cholecystokinin stimulates intestinal motility, gallbladder contraction,and biliary and pancreatic enzyme secretion, and is known to havetrophic actions on the pancreas thus increasing, inter alia, pancreaticenzyme production. Cholecystokinin also inhibits gastric emptying andhas various effects in the central nervous system, including regulationof appetite and pain. CCK regulates GI motility and specifically gut andcolonic motility. CCK promotes protein synthesis and cell growth,especially in the GI system and in the pancreas. CCK is involved inmediating satiety after a meal. CCK is an important neuromodulator andneurotransmitter involved in anxiety and panic disorder. CCK modulatesthe release of dopamine. CCK is also known to antagonize morphine andbeta-endorphine induced analgesia and the action on nociception.

Gastrin acts on CCK2 (otherwise known as gastrin/CCK-B receptors)whereas cholecystokinin acts on both CCK2 and CCK1 receptors (otherwiseknown as cholecystokinin/CCK-A receptors). Compounds that bind tocholecystokinin and/or gastrin receptors are important because of theirpotential pharmaceutical use as antagonists of the natural peptides ormimetics of the natural peptides acting as partial or full agonists atthe cholecystokinin and/or gastrin receptors. A selective gastrinreceptor antagonist has not yet been marketed. However, several arecurrently undergoing clinical evaluation. JB95008 (gastrazole) is beingdeveloped by The James Black Foundation and Johnson & JohnsonPharmaceutical Research & Development LLC for the potential treatment ofadvanced pancreatic cancer (pancreatic adenocarcinoma), and is currentlyin Phase II clinical trials. ML Laboratories and Panos are developingL-365,260 (Colycade), which is in Phase II clinical trials for pain.Other potential indications included eating disorders and cancer. YF-476(formerly YM-220), under joint development by Yamanouchi and FerringResearch Institute, is in Phase I clinical trials for gastro-esophagealreflux disease (GERD). In Phase I trials, Zeria Pharmaceutical isinvestigating Z-360, an orally available 1,5-benzodiazepine derivative(WO-09825911), as a potential treatment for gastroduodenal ulcers andreflux esophagitis. CR 2945 (itriglumide), an orally active anthranilicacid derivative, has been investigated by Rotta in Phase I trials foranxiety disorders, cancer (particularly colon cancer) and peptic ulcer.

Gastrimmune, Aphton Corporation's anti-gastrin vaccine, which works bychemical neutralization of the hormone, is undergoing late stageclinical trials for cancer indications, in particular, pancreatic andgastric tumors.

In addition to those indications described above, gastrin (CCK2)antagonists have been proposed for the following gastrin-relateddisorders: gastrointestinal ulcers, Barrett's esophagus, antral G cellhyperplasia, pernicious anaemia, Zollinger-Ellison syndrome, and otherconditions in which lower gastrin activity or lower acid secretion isdesirable.

Cholecystokinin (CCK1) receptors have been-shown to mediatecholecystokinin-stimulated gallbladder contraction, pancreatic enzymesecretion, satiety, gastric emptying inhibition and regulation ofperistalsis, indicating a key role in the integrated physiologicalgastrointestinal response to a meal. In addition, there is evidence thatcholecystokinin receptors mediate a mitogenic action of cholecystokininon some adenocarcinomas. Consequently, selective cholecystokininreceptor antagonists, for example, tarazepide, devazepide (Merck),lorglumide (Rotta), 2-NAP (JBF), dexloxiglumide (Rotta), and lintitript(Sanofi) have been examined in the clinic for potential applications in,inter alia, irritable bowel syndrome, chronic constipation, non-ulcerdyspepsia, acute and chronic pancreatitis, biliary disease andpancreatic cancer. Also, Kaken Pharmaceuticals and Mitsubishi-TokyoPharmaceuticals are awaiting registration in Japan on loxiglumide, aCCK-1 receptor antagonist for the treatment of GI cancers andpancreatitis. Loxiglumide is the racemate of dexloxiglumide.

A number of CCK-1 receptor agonists are under preclinical investigation.Glaxo Smith Kline, Inc. is investigating GW 5823, GW 7854, GW 7178 andGW 8573, 1,5-benzodiaepines for the treatment of gallstones,gastrointestinal disease and obesity. Also, Pfizer is investigating theCCK-1 receptor agonist, PD 170292, for obesity.

Additional roles of cholecystokinin receptors include the regulation ofappetite and metabolism, indicating potential therapeutic applicationsin the treatment of disorders such as obesity and anorexia nervosa.Other possible uses are in the potentiation of opiate (for examplemorphine) analgesia and in the treatment of cancers, especially of thepancreas. Moreover, ligands for cholecystokinin/gastrin receptors in thebrain have been claimed to possess anxiolytic activity, and gastrinreceptor antagonists would be expected to act as neurological agentstowards the relief of anxiety and related neuroses and psychoses.

Non-selective compounds that act as antagonists of both CCK-1 and CCK-2receptors are expected to offer the combined potential therapeuticapplications the selective antagonists described above with theadvantage of guaranteed synchronized action compared to the use of acombination of two selective compounds. These ‘dual’ or ‘mixed’ CCKreceptor antagonists are important because of their potentialpharmaceutical application for treatments of disorders where bothcholecystokinin and gastrin stimulated effects are implicated. Thus, acombination of the inhibition of the number of transient loweresophageal sphincter relaxations, reported to be under the control ofCCK-1 receptors (Boulant, J., et al. Gut, 1997, 40:575-581), togetherwith inhibition of CCK-2 receptor mediated gastric acid secretion andgastric mucosal growth might be expected to be valuable for thetreatment of gastrointestinal reflux disease. Similarly, the concurrentantagonism of cholecystokinin stimulated, CCK-1 receptor mediated,inhibition of gastric emptying together with inhibition of transientlower esophageal sphincter relaxations, gastric acid secretion andgastric mucosal growth might also be expected to be valuable for thetreatment of gastrointestinal or gastroesophageal reflux disease.Moreover, it has been hypothesized that CCK-1/CCK-2 receptor dualantagonists, such as those described by Fujisawa Pharmaceutical Co. Ltd.(Tabuchi, S., et al. Chem. Pharm. Bull. 2000, 48(1):1-15), will be moreefficacious for the treatment of pancreatitis than a selective CCK-1receptor antagonist alone as a consequence of inhibiting acid secretioninduced pancreatic enzyme release as well as cholecystokinin-stimulatedpancreatic enzyme release.

The features and advantages of the invention are apparent to one ofordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. Publications describedherein are incorporated by reference in their entirety.

Described herein is a series of aryl sulfonamide compounds with theability to modulate the activity of CCK1 and CCK2 receptors.

SUMMARY OF THE INVENTION

The invention features an aryl sulfonamide compound of formula (I):

wherein

-   X is C₁₋₂alkyl or a bond;-   R¹ is selected from the group consisting of    -   a) naphthyl, phenyl, said phenyl optionally fused at two        adjacent carbon atoms to R^(f),        -   R^(f) is a linear 3- to 5-membered hydrocarbon moiety having            0 or 1 unsaturated bonds and having 0, 1 or 2 carbon members            which is a carbonyl,    -   b) Ar⁶—, where Ar⁶ is a 6-membered heteroaryl having carbon as a        point of attachment, having 1 or 2 heteroatom members which are        —N═ and optionally benzo or pyrido fused,    -   c) Ar⁵—, where Ar⁵ is a 5-membered heteroaryl having carbon as a        point of attachment, having 1 heteroatom member selected from        the group consisting of O, S, >NH, and >NC₁₋₄alkyl, having 0 or        1 additional heteroatom member which is —N═ and optionally benzo        or pyrido fused,    -   d) Ar⁶⁻⁶—, where Ar⁶⁻⁶ is phenyl having the point of attachment        and fused to a 6-membered heteroaryl having 1 or 2 heteroatom        members which are —N═,    -   e) Ar⁶⁻⁵—, where Ar⁶⁻⁵ is phenyl or pyridyl having the point of        attachment and fused to a 5-membered heteroaryl having 1        heteroatom member selected from the group consisting of O,        S, >NH, and >NC₁₋₄alkyl, and having 0 or 1 additional heteroatom        member which is —N═,    -   where each of a) to e) is substituted with 0, 1, 2, or 3 of        R^(q),        -   R^(q) is independently selected from the group consisting of            —C₁₋₄alkyl, hydroxy, fluoro, chloro, bromo, iodo,            trifluoromethyl, nitro, cyano, aminoC₁₋₄alkyl,            C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl,            HO—C₁₋₄alkyl, C₁₋₄alkylO—C₁₋₄alkyl, HS—C₁₋₄alkyl,            C₁₋₄alkylS—C₁₋₄alkyl, C₁₋₄alkoxy, and C₁₋₄alkylS—;-   R² is selected from the group consisting of —H, —C₁₋₆-alkyl,    —C₂₋₆alkenyl, C₂₋₆alkynyl, —C₃₋₇cycloalkyl, and —C₃₋₇cycloalkenyl;-   R^(a) is, independently, selected from the group consisting of    —C₁₋₆-alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, furanyl,    thiophenyl, benzyl, pyrrol-1-yl, —OH, —OC₁₋₆-alkyl,    —OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆-alkyl,    —SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, cyano, nitro, —N(R^(y))R^(z)    (wherein R^(y) and R^(z) are independently —H, —C₁₋₄alkyl, or    C₁₋₆-cycloalkylC₁₋₄alkyl), —(C═O)C₁₋₄alkyl, —SCF₃, halo,    trifluoromethyl, —OCF₃, and —COOC₁₋₄alkyl, —COOH, or, alternatively,    two adjacent R^(a), may be taken together with the carbons of    attachment to form a fused ring selected from the group consisting    of phenyl, pyridyl, and pyrimidinyl;-   alternatively, R² and one of R^(a) may be taken together as —CHz-    or >C═O to form a fused ring to the phenyl;-   R^(b) is selected from the group consisting of 2,4-difluoro,    2,6-difluoro, or alternatively, two adjacent R^(b) substituents at    2- and 3-positions maybe taken together to form a five- or    six-membered heterocyclic ring selected from the group consisting of    oxazole, thiazole, thiadiazole, [1,3]dioxole, and pyrazine;-   R^(c) is independently selected from the group consisting of    hydrogen, —C₁₋₄alkyl, perhaloC₁₋₄alkyl, mono- or di-haloC₁₋₄alkyl,    aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl,    HO—C₁₋₄alkyl, HS—C₁₋₄alkyl, C₁₋₄alkylS—C₁₋₄alkyl,    —C₀₋₂alkylCOOC₁₋₄alkyl, —C₀₋₂alkylCOOH, and    —C₀₋₂alkylCON(R^(s))R^(t); —COO—C₀₋₂alkyl-ringA, and    —COO—C₁₋₂alkyl-CON(R^(s))R^(t);    -   R^(s) and R^(t) are independently selected from the group        consisting of —H, —C₁₋₄alkyl, C₁₋₆cycloalkylC₁₋₄alkyl, phenyl,        phenyl substituted with halo, benzyl, benzyl substituted with        halo,        -   or alternatively, R^(s) and R^(t) taken together with their            nitrogen of attachment form pyrrolidine, piperidine, or            morpholine;    -   ringA is selected from the group consisting of        -   i) a 6-membered heteroaryl having carbon as a point of            attachmnent and having 1 or 2 heteroatom members which are            —N═;        -   ii) a 5-membered heteroaryl having carbon as a point of            attachment, having 1 heteroatom member selected from the            group consisting of O, S, >NH, and >NC₁₋₄alkyl, and having 0            or 1 additional heteroatom member which is —N═; and        -   iii) a 5- or 6-membered non-aromatic heterocycle having a            carbon or nitrogen as a point of attachment, having 1 or 2            heteroatoms selected from the group consisting of O, S, and            N, having 0 or 1 double bonds, having 0 or 1 carbon member            replaced by a,carbonyl, and optionally substituted with            —C₁₋₄alkyl, —OH, or halo;-   R^(d) is independently selected from the group consisting of    hydrogen, —C₁₋₄alkyl, —OH, —OC₁₋₆alkyl, HO—C₁₋₄alkyl,    perhaloC₁₋₄alkyl, mono- or di-haloC₁₋₄alkyl, aminoC₁₋₄alkyl,    C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl, HS—C₁₋₄alkyl,    C₁₋₄alkylS—C₁₋₄alkyl, and optionally substituted phenyl; or two    R^(d) together can be ═O where at least one R^(c) is selected from    the group consisting of —COOC₁₋₄alkyl, —COO-ringA, -COOH,    —CON(R^(s))R^(t); and —COOC₁₋₂alkylCON(R^(s))R^(t);-   alternatively, one R^(c) and one R^(d) may be taken together to form    a double bond;-   and enantiomers, diastereomers, hydrates, solvates and    pharmaceutically acceptable salts, esters and amides thereof.

Isomeric forms of the compounds of formula (I), and of theirpharmaceutically acceptable salts, esters, and amides, are encompassedwithin the present invention, and reference herein to one of suchisomeric forms is meant to refer to at least one of such isomeric forms.One of ordinary skill in the art will recognize that compounds accordingto this invention may exist, for example in a single isomeric formwhereas other compounds may exist in the form of a regioisomeric orstereoisomeric mixture.

The present invention provides methods of treating or preventingdiseases and conditions mediated by the CCK1 and CCK2 receptors. Theinvention also features pharmaceutical compositions containing suchcompounds and methods of using,such compositions in the treatment orprevention of disease states mediated by dual CCK1 /CCK2 receptorantagonist activity.

Additional features and advantages of the invention will become apparentfrom the detailed description and examples below, and the appendedclaims.

DETAILED DESCRIPTION OF THE INVENTION

Particular preferred compounds of the invention comprise a compound ofFormula (I), or an enantiomer, diastereomer, hydrate, solvate thereof,or a pharmaceutically acceptable salt, amide or ester thereof, whereinR¹, R², R^(a), R^(b), R^(c), and R^(d) have any of the meanings definedhereinabove and equivalents thereof, or at least one of the followingassignments and equivalents thereof. Such assignments may be used whereappropriate with any of the definitions, claims or embodiments definedherein:

Preferably, X is a bond.

Preferably, R¹ is selected from the group consisting of

a) phenyl, naphthyl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-1,2,3 or4-yl, optionally 5,6,7,8 or 9 oxo substituted,5,6,7,8-tetrahydro-naphthalen-1,2,3 or 4-yl, optionally 5,6,7 or 8 oxosubstituted,

b) pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolin-2,3 or 4-yl,isoquinolin-1,3 or 4-yl, quinazolin-2 or 4-yl, quinoxalin-2 or 3-yl,naphthyridinyl,

c) furanyl, thiophenyl, 1-(H or C₁₋₄alkyl)pyrrolyl, oxazolyl, thiazolyl,pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, benzofuran-2 or 3-yl,benzothiophen-2 or 3-yl, 1-(H or C₁₋₄alky)-1H-indol-2 or 3-yl, 1-(H orC₁₋₄alkyl)-1H-benzimidazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl,1H-pyrrolopyridin-2 or 3-yl,

d) quinolin-5,6,7 or 8-yl, isoquinolin-5,6,7 or 8-yl, quinazolin-5,6,7or 8-yl, quinoxalin-5,6,7 or 8-yl, and

e) benzofuran-4,5,6 or 7-yl, benzothiophen-4,5,6 or 7-yl, 1-(H orC₁₋₄alkyl)-1H-indol-4,5,6 or 7-yl, 1-(H orC₁₋₄alkyl)-1H-benzimidazol-4,5,6 or 7-yl, benzooxazol-4,5,6 or 7-yl,benzothiazol-4,5,6 or 7-yl, 1H-pyrrolopyridin-4,5,6 or 7-yl, where eachof a) to e) is substituted with 0, 1, 2, or 3 of R^(q).

Most preferably, R¹ is selected from the group consisting of phenyl,6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl optionally 5,6,7,8 or 9 oxosubstituted, naphthyl, pyridyl, furanyl, thiophenyl, andbenzothiophenyl, where each member is substituted with 0, 1, 2, or 3 ofR^(q).

Specific R¹ are selected from the group consisting of phenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl,2,6-dichlorophenyl, 2,4,6-trichlorophenyl, 2-fluorophenyl,4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,2,6-difluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-4-fluorophenyl,2-fluoro-4-bromophenyl, 2-fluoro-4-chlorophenyl, 3-bromo-4-chlorophenyl,3-bromo-4-fluorophenyl, 4-chloro-3-iodophenyl, 2-methylphenyl,4-methylphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl,2-methylsulfanylphenyl, 2-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-nitrophenyl, 3-cyanophenyl, 4-cyanophenyl,naphthyl, thiophen-3-yl, 5-bromothiophen-3-yl, and benzothiophen-3-yl.

Preferably, R^(f) is selected from the group consisting of —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂— and —(C═O)CH₂CH₂CH₂—.

Preferably, R^(q) is selected from the group consisting of methyl,ethyl, propyl, t-butyl, hydroxy, fluoro, chloro, bromo, iodo,trifluoromethyl, nitro, cyano, aminomethyl, methylaminomethyl,dimethylaminomethyl, hydroxymethyl, methoxymethyl, methylsulfanyl,methylsulfanylmethyl, methoxy, ethoxy, mercaptomethyl, andmercaptoethyl.

Most preferably, R^(q) is selected from the group consisting of methyl,fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, and cyano.

Preferably, R² is selected from the group consisting of —H, methyl,ethyl, i-propyl, t-butyl, allyl, propargyl, cyclopropyl, cyclohexyl, andcyclopentenyl.

Preferably, R² and one of R^(a) are taken together as —CH₂— or >C═O toform a fused ring to the phenyl.

More preferably, R² is —H or methyl.

Preferably, each R^(a) is independently selected from the groupconsisting of methyl, ethyl, propyl, i-propyl, ethenyl, propenyl,cyclopropyl, cyclobutyl, phenyl, furanyl, thiophenyl, pyrrol-1-yl,benzyl, methoxy, ethoxy, propoxy, cyclopropoxy, cyclobutoxy,cyclopentoxy, phenoxy, benzoxy, mercapto, methylsulfanyl, ethylsulfanyl,t-butylsulfanyl, cyclopropylsulfanyl, phenylsulfanyl, nitro, cyano,amino, dimethylamino, (cyclohexylmethyl)amino, acetyl, —SCF₃, iodo,fluoro, chloro, bromo, trifluoromethyl, —OCF₃, and methoxycarbonyl.

Preferably, there is one R^(a). More preferably, there is one R^(a)positioned on the ring para to the amide substituent. Preferably, thereare two R^(a) substituents.

Preferably, where two adjacent R^(a) are taken together with the carbonsof attachment to form a fused ring, the fused ring is phenyl.

Most preferably, each R^(a) is independently selected from the groupconsisting of methyl, i-propyl, ethenyl, 2-propenyl, cyclopropyl,phenyl, thiophenyl, methoxy, ethoxy, propoxy, i-propoxy, nitro, cyano,dimethylamino, (cyclohexylmethyl)amino, acetyl, fluoro, chloro, bromo,iodo, —CF₃, and fused phenyl.

Preferably, two R^(b) are 2,6-difluoro or 2,4-difluoro.

Preferably, two adjacent R^(b) substituents at 2- and 3-positions aretaken with the benzene ring of attachment to form benzothiazole,benzothiadiazole, or quinoxaline.

Preferably, R^(c) is selected from the group consisting of hydrogen,methyl, ethyl, i-propyl, hydroxymethyl, methoxymethyl,dimethylaminomethyl, methylsulfanylmethyl, methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl, carboxy,carboxymethyl, carbamoyl, carbamoylmethyl, dimethylcarbamoyl,piperidine-1-carbonyl, 5-methyl-2-oxo-[1,3]dioxol-4-yl-methoxycarbonyl,3-pyridylmethoxycarbonyl, 3-chlorobenzylcarbamoyl,4-fluorobenzylcarbamoyl, benzylcarbamoyl, phenylcarbamoyl,dimethylcarbamoylmethoxycarbonyl, and 2-morpholin-4-ylethoxycarbonyl.

More preferably, R^(c) is selected from the group consisting ofhydrogen, methyl, hydroxymethyl, methoxycarbonyl, methoxycarbonylmethyl,carboxy, carboxymethyl, carbamoyl, and carbamoylmethyl.

Preferably, the,carbon to which the two R^(c) groups are attached is inthe (S) configuration.

Preferably, R^(d) is selected from the group consisting of hydrogen,methyl, ethyl, i-propyl, hydroxy, hydroxymethyl, methoxymethyl,dimethylaminomethyl, phenyl, 4-chlorophenyl, and methylsulfanylmethyl.

Preferably, two R^(d) together form ═O.

More preferably, R^(d) is selected from the group consisting ofhydrogen, methyl, phenyl, and hydroxy.

Compounds of Formula (I) comprise compounds that satisfy any one of thecombinations of definitions given herein and equivalents thereof.

It is understood that some compounds referred to herein are chiraland/or have geometric isomeric centers, for example E- and Z- isomers.The present invention encompasses all such optical isomers, includingdiastereomers and racemic mixtures, atropisomers, and geometric isomers,and mixtures thereof, that possess the activity that characterizes thecompounds of this invention. In addition, certain compounds referred toherein can exist in solvated as well as unsolvated forms. It isunderstood that this invention encompasses all such solvated andunsolvated forms that possess the activity that characterizes thecompounds of this invention.

Compounds according to the present invention that have been modified tobe detectable by some analytic technique are also within the scope ofthis invention. The compounds of the present invention may be labeledwith radioactive elements such as ¹²⁵I, ¹⁸F, ¹¹C, ⁶⁴Cu, ³H, ¹⁴C, and thelike for use in imaging or for radioactive treatment of patients. Anexample of such compounds is an isotopically labeled compound, such asan ¹⁸F isotopically labeled compound that may be used as a probe indetection and/or imaging techniques, such as positron emissiontomography (PET) and single-photon emission computed tomography (SPECT).Preferably, compounds of the present invention labeled with ¹⁸F or ¹¹Cmay be used as a positron emission tomography (PET) molecular probe forstudying CCK-mediated disorders. Alternatively, compounds of the presentinvention labeled with ¹⁴C maybe used in metabolic studies. Anotherexample of such compounds is an isotopically labeled compound, such as adeuterium and/or tritium labeled,compound that may be used in reactionkinetic studies. The compounds described herein may be reacted with anappropriate functionalized radioactive reagents using conventionalchemistry to provide radiolabeled compounds.

Preferred compounds of the present invention are selected from the groupconsisting of: EX Chemical Name 1(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(4-chloro-phenyl)-propyl]-benzamide; 2(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid; 32-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-phenyl-propionic acid; 4(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-phenyl)-propionic acid; 52-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide; 62-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2,2-bis-(4-chloro-phenyl)-ethyl]-4-chloro-benzamide; 72-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(4-chloro-phenyl)-2-methyl-propyl]-benzamide; 8(S)-3-(5-Bromo-thiophen-2-yl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid methyl ester; 9(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-naphthalen-2-yl-propionic acid; 10(±)-4-Chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-2-(2,4-difluorobenzenesulfonylamino)-benzamide; 11(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[1-carbamoyl-2-(4-chloro-phenyl)-ethyl]-4,5-dichloro-benzamide; 12(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-1-hydroxymethyl-ethyl]-4-methyl-benzamide; 13(S)-Benzo[1,2,5]thiadiazole-4-sulfonic acid[6-bromo-1,3-dioxo-2-(2-phenyl-propyl)-2,3-dihydro-1H-isoindol-4-yl]-amide; 14(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionic acid; 15(R)-3-(4-Chloro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid; 16(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide; 17(R)-2-[2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-3-phenyl-propionic acid; 18(±)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(3,4-dichloro-phenyl)-3-oxo-propionic acid methyl ester; 192-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionic acid; 202-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-methyl-N-phenethyl-benzamide; 212-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-[2-(4-chloro-phenyl)-propyl]-benzamide; 222-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-1-methyl-ethyl]-4-trifluoromethyl-benzamide; 232-(Benzothiazole-4-sulfonylamino)-4-bromo-N-[2-(4-chloro-phenyl)-1-methyl-ethyl]-benzamide; 244-Bromo-N-[2-(4-chloro-phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-benzamide; 252-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-phenyl-propionic acid; 262-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-trifluoromethyl-benzoylamino]-3-phenyl-propionic acid; 272-[4-Iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-phenyl-propionicacid; 282-[2-(Benzothiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-phenyl-propionic acid; 292-[4,5-Dichloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-phenyl-propionic acid; 304-Bromo-N-[2-(3,4-dichloro-phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-benzamide; 312-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-(2-phenyl-propyl)-benzamide; 323-(3,4-Dichloro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-propionic acid; 332-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-propionic acid; 343-(4-Chloro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-propionic acid; 35(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-(2-phenyl-propyl)-benzamide; 36(R)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-(2-phenyl-propyl)-benzamide; 37(S)-4-Bromo-2-(2,6-difluoro-benzenesulfonylamino)-N-(2-phenyl-propyl)-benzamide; 38(R)-4-Bromo-2-(2,6-difluoro-benzenesulfonylamino)-N-(2-phenyl-propyl)-benzamide; 392-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(3,4-dichloro-phenyl)-propyl]-4-iodo-benzamide; 40N-[2-(3,4-Dichloro-phenyl)-propyl]-4-iodo-2-(quinoxaline-5-sulfonylamino)-benzamide; 412-[4-Bromo-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino]-3-(2,4-dichloro-phenyl)-propionic acid; 42N-[2-(3,4-Dichloro-phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzamide; 434-Chloro-N-[2-(2,4-dichloro-phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-benzamide; 444-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-N-[2-(4-nitro-phenyl)-propyl]-benzamide; 454-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-N-[2-(4-trifluoromethyl-phenyl)-propyl]-benzamide; 462-[4-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino]-3-(2,4-dichloro-phenyl)-propionic acid; 47N-[2-(2,4-Dichloro-phenyl)-propyl]-2-(2,6-difluoro-benzensulfonylamino)-4-iodo-benzamide; 482-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-N-[2-(4-nitro-phenyl)-propyl]-benzamide; 492-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-((2S,1R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-benzamide; 502-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-indan-2-yl-benzamide; 512-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-methyl-N-(2-pyridin-2-yl-ethyl)-benzamide hydrochloride; 52(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(4-chloro-phenyl)-1-hydroxymethyl-ethyl]-benzamide; 53(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-[2-(4-chloro-phenyl)-1-methyl-ethyl]-benzamide; 54(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-propyl]-4-methyl-benzamide; 552-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[(1R,2S)-2-(4-chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-benzamide; 56(2S,3R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-butyric acid; 57(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide; 58(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide; 59(±)-4-Chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-2-(quinoxaline-5-sulfonylamino)-benzamide; 60(R)-3-(3,4-Dichloro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid; 61(±)-N-[2-(3,4-Dichloro-phenyl)-propyl]-4-iodo-2-(quinoxaline-5-sulfonylamino)-benzamide; 62(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoylamino]-3-(4-chloro-phenyl)-propionic acid; 63(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(3-cyano-phenyl)-propionic acid; 64(S)-3-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-4-(3,4-dichloro-phenyl)-butyric acid; 65(S)-3-Benzo[b]thiophen-3-yl-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid methyl ester; 66(S)-3-Benzo[b]thiophen-3-yl-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid; 67(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionic acid methyl ester; 68(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionic acid; 69(R)-2-[4-Chloro-2-(2,4-difluoro-benzenesulfonylamino)-benzoylamino]-3-(4-chloro-phenyl)-propionic acid methyl ester; 702-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(2,4-dichloro-phenyl)-ethyl]-benzamide; 71(S)-2-[4-Chloro-2-(2,4-difluoro-benzenesulfonylamino)-benzoylamino]-3-(4-chloro-phenyl)-propionic acid methyl ester; 722-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-propyl]-4-iodo-benzamide; 73(R)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-(2-hydroxy-1-methyl-2,2-diphenyl-ethyl)-benzamide; 74(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-(2-hydroxy-1-methyl-2,2-diphenyl-ethyl)-benzamide; 752-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(2,4-dichloro-phenyl)-ethyl]-benzamide; 76(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(4-fluoro-phenyl)-propionic acid; 77(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-thiophen-3-yl-propionic acid; 78(S)-3-(3-Chloro-phenyl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid; 79(S)-2-[4-Iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-p-tolyl-propionic acid; 80N-[2-(4-Bromo-phenyl)-ethyl]-4-chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzamide; 812-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-6-chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide; 82(R)-3-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-4-(3,4-dichloro-phenyl)-butyric acid; 83(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoylamino]-3-(4-chloro-phenyl)-propionic acid; 84(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(3-nitro-phenyl)-propionic acid; 85(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(3,4-difluoro-phenyl)-propionic acid; 86(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(4-cyano-phenyl)-propionic acid; 87(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-thiophen-3-yl-propionic acid; 88(S)-4-(4-Chloro-phenyl)-3-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-butyric acid methyl ester; 89(S)-4-(4-Chloro-phenyl)-3-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-butyric acid; 90(S)-3-(4-Chloro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid; 91(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionic acid; 92(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-3-iodo-phenyl)-propionic acid; 93(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid; 94(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionic acid; 95(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyric acid; 962-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-2-methyl-propionic acid; 972-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-phenyl)-propionic acid; 982-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-3-hydroxy-propionic acid; 992-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[(2S,1R)-2-(4-chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide; 1002-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(3,4-dichloro-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide; 1012-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[(2S,1R)-2-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide; 1022-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionic acid; 1032-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-phenyl)-butyric acid; 1042-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(3-bromo-phenyl)-propyl]-4-iodo-benzamide; 1052-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-acrylic acid; 106(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionic acid; 107(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyric acid; 1082-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[(2S,1R)-2-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-4-chloro-benzamide; 1092-[2-(Benzooxazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionic acid; 1102-[2-(Benzooxazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid; 1112-[2-(Benzo[1,3]dioxole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid; 1122-(Benzo[1,3]dioxole-4-sulfonylamino)-4-chloro-N-[2-(4-chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-benzamide; 1132-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester; 1142-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid pyridin-3-ylmethyl ester; 115(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-phenyl)-propionic acid; 116(2S,3R)-3-(3,4-Dichloro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-butyric acid methyl-ester; 117(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid; 118(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid; 119(S)-2-[4-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid; 120(R)-2-[4-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid; 121anti-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionic acid; 122(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionic acid methyl ester; 123(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid methyl ester; 124(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid methyl ester; 125(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-propionic acid methyl ester; 126(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid; 127(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-propionic acid; 128(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[1-(3-chloro-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethyl]-benzamide; 129(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[1-benzylcarbamoyl-2-(3,4-dichloro-phenyl)-ethyl]-4-chloro-benzamide; 130(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(3,4-dichloro-phenyl)-1-(4-fluoro-benzylcarbamoyl)-ethyl]-benzamide; 131(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid; 132(S)-3-(3,4-Dichloro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid; 133(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(2,4-dichloro-phenyl)-propionic acid; 134(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(2,4-dichloro-5-fluoro-phenyl)-propionic acid; 135(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-iodo-phenyl)-propionic acid; 136(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-3-iodo-phenyl)-propionic acid methyl ester; 137(S)-3-(4-Chloro-3-iodo-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid methyl ester; 138(S)-3-(4-Chloro-3-iodo-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid; 139(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(3,4-dichloro-phenyl)-1-phenylcarbamoyl-ethyl]-benzamide; 140(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[1-(3,4-dichloro-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-benzamide; 141(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid; 142(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionic acid methyl ester; 143(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid methyl ester; 144(Z)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3,4-dichloro-phenyl)-acrylic acid; 145(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionic acid; 146(S)-3-(3-Bromo-4-chloro-phenyl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid; 147(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino] 3-(3-bromo-4-chloro-phenyl)-propionic acid; 148(S)-3-(3-Bromo-4-chloro-phenyl)-2-[4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid; 149(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid methyl ester; 150(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid methyl ester;151(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-bromo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid methyl ester; 152(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-chloro-2-quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid methyl ester; 153(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid methyl ester; 154(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid methyl ester; 155(S)-3-(3-Bromo-4-chloro-phenyl)-2-[4-bromo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid; 156(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid; 157(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid; 158(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-bromo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid; 159(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid; 160(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid; 161(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionic acid; 162(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid; 163(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid ethyl ester;1642-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionic acid; 1652-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-3-iodo-phenyl)-propionic acid; 1662-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid; 1672-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionic acid; 1682-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyric acid; 1692-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide; 1702-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide; 1712-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionic acid; 1722-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyric acid; 1732-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-4-chloro-benzamide; 174(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid tert-butylester; 175(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid2-morpholin-4-yl- ethyl ester; and 176(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic aciddimethylcarbamoylmethyl ester.

The compounds as described above may be made according to processeswithin the skill of the art and/or that are described in the schemes andexamples that follow. To obtain the various compounds herein, startingmaterials may be employed that carry the ultimately desired substituentsthough the reaction scheme with or without protection as appropriate.This may be achieved by means of conventional protecting groups, such asthose described in “Protective-Groups in Organic Chemistry”, ed. J. F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts,“Protective Groups in Organic Synthesis”, 3^(rd) ed., John Wiley, Sons,1999. The protecting groups may be removed at a convenient subsequentstage using methods known from the art. Alternatively, it may benecessary to employ, in the place of the ultimately desired substituent,a suitable group that may be carried through the reaction scheme andreplaced as appropriate with the desired substituent. Such compounds,precursors, or prodrugs are also within the scope of the invention.Reactions may be performed between the melting point and the refluxtemperature of the solvent, and preferably between 0° C. and the refluxtemperature of the solvent.

The compounds of Formula (I) may be prepared by a number of reactionschemes. Persons skilled in the art will recognize that certaincompounds are more advantageously produced by one scheme as compared toanother. Table of Acronyms Term Acronym Tetrahydrofuran THFN,N-Dimethylformamide DMF Dimethyl sulfoxide DMSO tert-ButylcarbamoylBoc High-pressure liquid chromatography HPLC Acetyl Ac Ethyl acetateEtOAc Trifluoroacetic acid TFA Methanesulfonyl chloride MsClDichloromethane DCM O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′- HATUtetramethyluronium hexafluorophosphate1,5,7-Triazabicyclo[4.4.0]dec-5-ene TBD 4-(Dimethylamino)pyridine DMAP

Referring to Scheme A, commercially available aminobenzoic acid A1 isreacted with triphosgene and Hünig's base to produce the benzofusedisatoic anhydride species of the genus A2. Various isatoic anhydrides A2are available commercially. An amine is acylated with the isatoicanhydride A2 to produce a benzamide A5. Benzamide A5 may also beobtained from commercially available anthranilic acid A3 through peptidecoupling with amines A7. Benzamide A5 may additionally be obtainedfrom,commercially available nitrobenzoic acid A4 through peptidecoupling with amines A7, followed by reduction of the nitro group.Benzamide A5 is sulfonylated with aryl sulfonyl chloride A6 to producearyl sulfonamide compounds (I).

Referring to Scheme B, methyl anthranilate B1 is sulfonylated tosulfonamide B2. The methyl (or other alkyl) ester is hydrolyzed to theacid B3. Acid B3 undergoes peptide coupling with amine A7 under standardconditions to produce compounds of Formula (I).

Referring to Scheme C, phenol C1 is acylated with thionocarbamoylchloride producing a thionocarbamate. The thionocarbamate is isomerizedby heating to thiocarbamate C3, where good yields are obtained withheating to 240 C for about 45 minutes. Finally, the thiocarbamate issaponified to the corresponding thiol and immediately thereafteroxidized to the sulfonylchloride A6. Additionally, some sulfonylchlorides may be commercially available.

Amines of Formula A7 may be commercially available or may be preparedaccording to methods described in Schemes D-I.

Referring to Scheme D, a carboxylic acid or derivative of type D1 (whereX′ is OH, OC₁₋₄alkyl, a protecting group, or a chiral auxiliary) issingly or multiply alkylated with an activated halide containing groupR^(d) and subsequently converted to an amine D3 by methods well known inthe art. Where X′ is a chiral auxiliary, and where the R^(d)substituents differ from one another, particular non-racemic productsare obtained.

Referring to Scheme E, an amine of type E1 is converted to E3 viaalkylation with an R^(d)-containing electrophile, followed by removal ofX″, if necessary. X″ is absent or is a protecting group or a chiralauxiliary. The amine group “N═PG” may be a free amine, a suitablyprotected amine such as a Boc-protected amine or other carbamate, or animine such as that derived from benzophenone. In the case where X″ is achiral directing group, non-racemic E2 and E3 may also be produced.Where R^(c)—X″ is a t-butyl ester, alkylation may be performed in thepresence of a chiral catalyst to produce non-racemic E2 and E3. Aparticular embodiment is described in Example 174. Preferably, saidalkylation is performed in the presence ofO-allyl-N-(9-anthracenylmethyl)-cinchonidinium bromide, at reducedtemperature, and with a suitable base such as CsOH.H₂O. Alternatively,alkene E4 is,converted directly to E3 via addition of the groups R^(d)and ammonia or an ammonia equivalent across the double bond.Alternatively, alkene E4 is converted in a similar manner to alcohol E5,and subsequently to an amine E3 using methods known to those skilled inthe art.

Referring to Scheme F, R^(d) is introduced to an unsaturated aldehyde(F1) by 1,4-addition to provide F2. An aldehyde of formula F2 is thenelectrophilically aminated to form an amino aldehyde F3. Oxidation andfunctionalization of the aldehyde produces a carboxylic acid or acarboxylate derivative such as F4, where Y is OH, OC₁₋₄alkyl, orN(R^(y))(R^(z)). A carboxylic acid analog of formula F4 may besubsequently reduced to the corresponding primary alcohol F5.

Referring to Scheme G, a carboxylic acid derivative such as an acidhalide G1, where Hal is preferably chloride, reacts with an isonitrileto provide oxazole G2. Oxazole G2 is then hydrolyzed to an amino ketoneof formula-G3, where X is a bond. G3, in turn, is modified via additionof R^(d) to the carbonyl to form G4, or reduced to G6 (where X is abond) using methods well known in the art. Alternatively, the reductionof a ketone of type G3 to an alcohol of type G6,is performed after ketoamine G3 is coupled to the anthranilic portion as described in Schemes Aand B. An amine of type G5, or a nitrogen-protected analog, is condensedwith a suitable aldehyde (where X is C₁₋₂alkyl or a bond) to form anamino alcohol G6. An alkene G7 may be prepared by dehydration of amineG6 or by condensation of an aldehyde with an appropriately derivatizedamine, or nitrogen-protected analog, of the type G8 (preferably, whereG8 is a phosphorous ylid).

Referring to Scheme H, single or multiple alkylation of carboxylic acidderivative H1 provides H2, which is converted to amine H3 using methodsknown to those skilled in the art. Substituent X′ is as defined above.Alternatively, carboxylic acid derivative H1 is aminated to provideamine H4 using methods well known in the art. Conversion of H4 to aminoacid derivative H5 gives compounds of Formula (I) where Y is definedpreviously. Where X′ is a chiral auxiliary, certain non-racemic productsmay be obtained.

Referring to Scheme I, alkylation of a protected 2-amino malonic acidderivative 12 with an alkyl chloride or other alkylating agent I1, inthe presence of a base such as NaOEt, provides diesters I5. Hydrolysisand decarboxylation using standard methods gives amino acids I4.Selective deacetylization with a suitable enzyme, such as acylase fromAsperigillus genus, allows for the isolation of non-racemic I5 and I6.The desired material may be further processed according to the precedingschemes to provide compounds of Formula (I). A particular embodiment isshown in Intermediate Example 1. Enzymatic resolution is preferablyperformed with the following conditions: in water, at a pH ofapproximately 8, in the presence of CoCl₂, and at 40° C. Preferably, the“L” enantiomer (I6) is obtained in greater than 90% ee. More preferably,the “L” enaantiomer (I6) is obtained in greater than 95% ee. Even morepreferably the “L” enantiomer (I6) is obtained in greater than 99% ee.

Compounds of Formula (I) may be converted to their corresponding saltsusing methods known to those skilled in the art. For example, amines ofFormula (I) may be treated with trifluoroacetic acid, HCl, or citricacid in a solvent such as MeOH to provide the corresponding salt forms.Acids of Formula (I) may be treated with NaOH or KOH to provide thecorresponding salt forms.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, or asracemic mixtures or mixtures of enantiomers, diastereomers, orregioisomers. Where regioisomeric or diastereomeric mixtures areobtained, isomers maybe separated using conventional methods such aschromatography or crystallization. Where. racemic (1:1) and non-racemic(not 1:1) mixtures of enantiomers are obtained, single enantiomers maybe isolated using conventional separation methods known to one skilledin the art. Particularly useful separation methods may include chiralchromatography, recrystallization, resolution, diastereomeric saltformation, or derivatization into diastereomeric adducts followed byseparation.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with a compound of Formula(I) or with a compound that converts to a compound of Formula (I) invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in “Design of Prodrugs”, ed. H. Bundgaard,Elsevier, 1985; Beaumont; K.; Webster, R.; Gardner, I.; Dack, K. ]Curr.Drug Metab. 2003, 4, 461-485; Mizen, L; Burton, G. Pharm. Biotechnol.1998, 11, 345-365. In addition to prodrugs, the invention provides thesalts,.esters, amides, and other protected or derivatized forms of thedescribed compounds.

For therapeutic use, salts of the compounds of the present invention arethose that are pharmaceutically acceptable. However, salts of acids andbases that are non-pharmaceutically acceptable may also find use, forexample, in the preparation or purification of a pharmaceuticallyacceptable compound. All salts, whether pharmaceutically acceptable ornot are included within the ambit of the present invention.

Pharmaceutically acceptable salts, esters, and amides of compoundsaccording to the present invention refer to those salt, ester, and amideforms of the compounds of the present invention which would be apparentto the pharmaceutical chemist, i.e., those that are non-toxic and thatwould favorably affect the pharmacokinetic properties of said compoundsof the present invention. Those compounds having favorablepharmacokinetic properties would be apparent to the pharmaceuticalchemist, i.e., those which are non-toxic and which possess suchpharmacokinetic properties to provide sufficient palatability,absorption, distribution, metabolism and excretion. Other factors, morepractical in nature, which are also important in the selection, are costof raw materials, ease of crystallization, yield,. stability,hygroscopicity and flowability of the resulting bulk drug.

Examples of acids that may be used in the preparation ofpharmaceutically acceptable salts include the following: acetic acid,2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginicacid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoicacid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid,camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid,caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid,cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaricacid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid,hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionicacid, lauric acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Compounds of the present invention containing acidic protons maybeconverted into their therapeutically active non-toxic metal or amineaddition salt forms by treatment with appropriate organic and inorganicbases. Appropriate base salt forms comprise, for example, the ammoniumsalts; the alkali and earth alkaline metal salts (e.g. lithium, sodium,potassium, magnesium, calcium salts, which may be prepared by treatmentwith, for example, magnesium hydroxide, calcium hydroxide, potassiumhydroxide, zinc hydroxide, or sodium hydroxide); and amine salts madewith organic bases (e.g. primary, secondary and tertiary aliphatic andaromatic amines such as L-arginine, benethamine, benzathine, choline,deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine,diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine,ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,methylamine, piperidine, piperazine, propylamine, pyrrolidine,1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,isoquinoline, secondary amines, triethanolamine, trimethylamine,triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine). See, e.g.,S. M. Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977,66:1-19, and Handbook of Pharmaceutical Salts, Propertions, Selection,and Use; Stahl, P. H., Wermuth, C. G., Eds.; Wiley-VCH and VHCA: Zurich,2002, which are incorporated herein by reference.

Pharmaceutically acceptable esters and amides are those that are withina reasonable benefit/risk ratio, pharmacologically effective andsuitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response. Representativepharmaceutically acceptable amides of the invention include thosederived from ammonia, primary C₁₋₆alkyl amines and secondarydi(C₁₋₆alkyl) amines. Secondary amines include 5- or 6-memberedheterocyclic or heteroaromatic ring moieties containing at least onenitrogen atom and optionally between 1 and 2 additional heteroatoms.Preferred amides are derived from ammonia, C₁₋₃alkyl primary amines, anddi(C₁₋₂alkyl)amines.

Representative pharmaceutically acceptable esters of the inventioninclude C₁₋₇alkyl, C₅₋₇Cycloalkyl, phenyl, substituted phenyl, andphenylC₁₋₆alkyl-esters. Preferred esters include methyl esters.Furthermore, examples of suitable esters include such esters where oneor more carboxyl substituents is replaced withp-methoxybenzyloxy-carbonyl, 2,4,6-trimethylbenzyloxy-carbonyl,9-anthryloxycarbonyl, CH₃SCH₂COO—, tetrahydrofur-2-yloxycarbonyl,tetrahydropyran-2-yloxy-carbonyl, fur-2-yloxycarbonyl,benzoylmethoxy-carbonyl, p-nitrobenzyloxy-carbonyl,4-pyridylmethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, t-butyloxycarbonyl, t-amyloxy-carbonyl,diphenylmethoxycarbonyl, triphenylmethoxycarbonyl,adamantyloxy-carbonyl, 2-benzyloxyphenyloxycarbonyl,4-methylthiophenyloxycarbonyl, or tetrahydropyran-2-yloxycarbonyl.

The compounds of the present invention are dual CCK1/CCK2 antagonists. Adual CCK1/CCK2 antagonist is useful in methods for treating a disordermediated by the CCK1 or CCK2 receptor. Compounds of the presentinvention therefore may be useful in methods for treating or preventingpain, drug dependence, anxiety, panic attack, schizophrenia, pancreaticdisorders, secretory disorders, gastrointestinal motility disorders,functional bowel disease, biliary colic, cancer, eating disorders(including, for example, anorexia), reflux diseases (including, forexample, gastro-esophageal reflux disease and non-erosive refluxdisease), gastroduodenal ulcers, reflux esophagitis, peptic ulcers,Barrett's esophagus, antral G cell hyperplasia, pernicious anaemia andZollinger-Ellison syndrome. Cancer includes, for example, colon cancer,pancreatic adenocarcinoma, pancreatic tumors, and gastric tumors.

Particularly, dual CCK1/CCK2 antagonists are useful in methods fortreating or preventing pancreatic adenocarcinoma, pain,gastro-esophageal reflux disease, non-erosive reflux disease, anorexia,pancreatitis, gastroduodenal ulcers, reflux esophagitis, anxiety, coloncancer, peptic ulcers, pancreatic tumors and gastric tumors.

Said methods of treating and preventing comprise the step ofadministering to a mammal suffering therefrom an effective amount of atleast one compound of the present invention.

Compounds of the present invention may be administered in pharmaceuticalcompositions to treat patients (humans and other mammals) with disordersmediated by the CCK1 and CCK2 receptors. Thus, the invention featurespharmaceutical compositions containing at least one compound of thepresent invention and a pharmaceutically acceptable carrier. Acomposition of the invention may further include at least one othertherapeutic agent (for example, a combination formulation or combinationof differently formulated active agents for use in a combination therapymethod).

The present invention also features methods of using or preparing orformulating such pharmaceutical compositions. The pharmaceuticalcompositions can be prepared using conventional pharmaceuticalexcipients and compounding techniques known to those skilled in the artof preparing dosage forms. It is anticipated that the compounds of theinvention can be administered by oral, parenteral, rectal, topical, orocular routes, or by inhalation. Preparations may also be designed togive slow release of the active ingredient. The preparation may be inthe form of tablets, capsules, sachets, vials, powders, granules,lozenges, powders for reconstitution, liquid preparations, orsuppositories. Preferably, compounds may be administered by intravenousinfusion or topical administration, but more preferably by oraladministration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. Tablets for oral use may include the active ingredient mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservatives. Suitableinert fillers include sodium and calcium carbonate, sodium and calciumphosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesiumstearate, mannitol, sorbitol, and the like; typical liquid oralexcipients include ethanol, glycerol, water and the like. Starch,polyvinyl-pyrrolidone, sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, will generally be magnesium stearate, stearic acid or talc. Ifdesired, the tablets may be coated with a material such as glycerylmonostearate or glyceryl distearate to delay absorption in thegastrointestinal tract, or may be coated with an enteric coating.Capsules for oral use include hard gelatin capsules in which the activeingredient is mixed with a solid, semi-solid, or liquid diluent, andsoft gelatin capsules wherein the active ingredient is mixed with water,an oil such as peanut oil or olive oil, liquid paraffin, a mixture ofmono and di-glycerides of short chain fatty acids, polyethylene glycol400, or propylene glycol.

Liquids for oral administration may be suspensions, solutions, emulsionsor syrups or may be presented as a dry product for reconstitution withwater or other suitable vehicles before use. Compositions of such liquidmay contain pharmaceutically-acceptable excipients such as suspendingagents (for example, sorbitol, methyl cellulose, sodium alginate,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel and the like); non-aqueous vehicles, which include oils(for example, almond oil or fractionated coconut oil), propylene glycol,ethyl alcohol or water; preservatives (for example, methyl or propylp-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and,if needed, flavoring or coloring agents.

The compounds of this invention may also be administered by non-oralroutes. The compositions may be formulated for rectal administration asa suppository. For parenteral use, including intravenous, intramuscular,intraperitoneal, or subcutaneous routes, the compounds of the inventionwill generally be provided in sterile aqueous solutions or suspensions,buffered to an appropriate pH and isotonicity or in parenterallyacceptable oil. Suitable aqueous vehicles include Singer's solution andisotonic sodium chloride. Such forms will be presented in unit dose formsuch as ampules or disposable injection devices, in multi-dose formssuch as vials from which the appropriate dose may be withdrawn, or in asolid form or pre-concentrate that can be used to prepare an injectableformulation. Another mode of administration of the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery. The compounds of this invention may also be administered byinhalation, via the nasal or oral routes using a spray formulationconsisting of the compound of the invention and a suitable carrier.

Methods are known in the art for determining effective doses fortherapeutic (treatment) and prophylactic (preventative) purposes for thepharmaceutical compositions or the drug combinations of the presentinvention, whether or not formulated in the same composition. Thespecific dosage level required for any particular patient will depend ona number of factors, including severity of the condition being treated,the route of administration, and the weight of the patient. Fortherapeutic purposes, “effective dose” or “effective amount” refers tothat amount of each active compound or pharmaceutical agent, alone or incombination, that elicits the biological or medicinal response in atissue system, animal, or human that is being sought by a researcher,veterinarian, medical doctor, or other clinician, which includesalleviation of the symptoms of the disease or disorder being treated.For prophylactic purposes (i.e., preventing or inhibiting the onset orprogression of a disorder), the term “effective dose” or “effectiveamount” refers to that amount of each active compound or pharmaceuticalagent, alone or in combination, that inhibits in a subject the onset orprogression of a disorder as being sought by a researcher, veterinarian,medical doctor, or other clinician, the delaying of which disorder ismediated, at least in part, by the modulation of the CCK1 and CCK2receptors. Methods of combination therapy include co-administration of asingle formulation containing all active agents; essentiallycontemporaneous administration of more than one formulation; andadministration of two or more active agents separately formulated.

It is anticipated that the daily dose (whether administered as a singledose or as divided doses) will be in the range 0.01 to 1000 mg per day,more usually from 1 to 500 mg per day, and most usually from 10 to 200mg per day. Expressed as dosage per unit body weight, a typical dosewill be expected to be between 0.0001 mg/kg and 15 mg/kg, especiallybetween 0.01 mg/kg and 7 mg/kg, and most especially between 0.15 mg/kgand 2.5 mg/kg.

Preferably, oral doses range from about 0.05 to 200 mg/kg, daily, takenin 1 to 4 separate doses. Some compounds of the invention may be orallydosed in the range of about 0.05 to about 50 mg/kg daily, others may bedosed at 0.05 to about 20 mg/kg daily, while still others may be dosedat 0.1 to about 10 mg/kg daily. Infusion doses can range from about 1 to1000 μg/kg/min of inhibitor, admixed with a pharmaceutical carrier overa period ranging from several minutes to several days. For topicaladministration compounds of the present invention may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle.

EXAMPLES

In order to illustrate the invention, the following examples areincluded. These examples do not limit the invention. They are only meantto suggest a method of practicing the invention. Those skilled in theart may find other methods of practicing the invention, which areobvious to them. However, those methods are deemed to be within thescope of this invention.

Preparative reversed-phase HPLC was performed on a Gilson® instrument,using a YMC-Pack ODS-A, 5μm 75×30 mm column, with a flow rate of 10mL/min, and detection at λ 220 and 254 nm. The gradient was 20 to 99%acetonitrile/water/0.05% TFA over 20 min.

For analytical reversed-phase HPLC, a Hewlett Packard Series 1100 wasused, with an Agilent ZORBAX® C8, 5μm, 4.6×150 mm column, a flow rate of1 mL/min, and detection at λ 220 and 254 nm. The gradient was 1 to 99%acetonitrile/water/0.05% TFA over 8 min.

Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative modes asindicated. The calculated (calcd.) mass corresponds to the exact mass.

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz) orDPX500 (500 MHz) spectrometer. The format of the ¹H NMR data below is:chemical shift in ppm down field of the tetramethylsilane reference(multiplicity, coupling constant J in Hz, integration).

Normal phase flash chromatography was performed using Isco® RediSep™ 4,12, 40 or 120 g cartridges under medium pressure.

Elemental analyses were performed by NuMega Resonance Labs, Inc., SanDiego, Calif.

Where solutions were “concentrated”, they were concentrated underseduced pressure using a rotary evaporator.

Example 1

(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(4-chloro-phenyl)-propyl]-benzamide

A. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acidmethyl ester. To a solution of methyl 2-amino-4-chlorobenzoate (7.0 g,37.7 mmol) in DCM (75 mL) at room temperature (rt) was added4-chlorosulfonyl-2,1,3-benzothiadiazole 49.45 g, 39.6 mmol), pyridine(9.1 mL, 112 mmol), and DMAP (0.23 g, 1.88 mmol). The mixture wasstirred at rt overnight, poured into 1 N HCl (200 mL), and extractedwith DCM (2×100 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated. The crude residue was purified by flash chromatography(hexanes/EtOAc) to afford the title sulfonamide as a tan solid (11.65 g,80%). MS (ESI−): mass calcd. for C₁₄H₁₀ClN₃O₄S₂, 383.8; m/z found, 382[M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.38 (s, 1H), 8.40 (dd, J=7.2, 1.2,1H), 8.24 (dd, J=8.8, 1.2, 1H), 7.80 (d, J=8.4, 1H), 7.76 (d, J=2.0,1H), 7.74 (dd, J=8.8, 7.2, 1H), 6.94 (dd, J=8.4, 2.0, 1H), 3.92 (s, 3H).Anal. calcd. for C₁₄H₁₀ClN₃O₄S₂: C, 43.81; H, 2.63; N, 10.95. Found: C,44.19; H, 3.00; N, 11.23.

B. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid. Toa stirred suspension of2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid methylester (2.0 g, 5.2 mmol) in THF (12 mL) at rt was added LiOH (2 M inwater, 10 mL). The resulting orange mixture was stirred overnight at rtthen poured into 0.5 M HCl (150 mL) causing precipitation of the desiredbenzoic acid. After stirring the mixture several minutes to completeprecipitation, the product was collected by suction filtration andair-dried to afford the acid as a tan solid (1.87 g, 97%). MS (ESI−):mass calcd. for C₁₃H₈ClN₃O₄S₂, 369.8; m/z found, 368 [M−H]⁻. ¹H NMR (400MHz, CDCl₃): 11.22 (br s, 1H), 8.43 (dd, J=7.2, 1.0, 1H), 8.26 (dd,J=8.8, 1.0, 1H), 7.90(d, J=8.8, 1H), 7.80 (d, J=2.0, 1H), 7.75 (dd,J=8.8, 7.2, 1H), 6.99 (dd, J=8.8, 2.0, 1H). Anal. calcd. forC₁₃H₈ClN₃O₄S₂: C, 42.22; H, 2.18; N, 11.36. Found: C, 41.92; H, 2.50; N,11.38.

C.(±)-2-(Benzo[1.2.5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(4-chloro-phenyl)-propyl]-benzamide.To a solution of2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid (0.030g, 0.081 mmol) in a mixture of THF (0.12 mL) and DMF (0.60 mL) at rt wasadded pyridine (0.020 mL, 0.25 mmol) followed by HATU (0.062 g, 0.17mmol). The reaction mixture was agitated for 1 h on a shaker.(±)-2-(4-Chlorophenyl)-propylamine hydrochloride (0.035 g, 0.17 mmol)and N,N-diisopropylethylamine (Hünig's base; 0.030 mL, 0.17 mmol) wereadded. (Hünig's base may be omitted when using the free base form of theamine.) The reaction mixture was agitated for 1 h. TFA (0.050 mL) wasadded to quench the reaction. The mixture was diluted with DMF (1 mL),and the product amide was obtained by purification of the resultingmixture by preparative reverse-phase HPLC. The title amide was obtainedas a solid (27 mg, 64%). HPLC: R_(T)=10.60 min. MS (ESI−): mass calcd.for C₂₂H₁₈Cl₂N₄O₃S, 520.02; m/z found, 519/521 [M−H]⁻. ¹H NMR (500 MHz,CDCl₃): 11.53 (s, 1H), 8.35 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0,1H), 7.71 (dd, J=8.8, 7.0, 1H), 7.70 (d, J=2.0, 1H), 7.32-7.27 (m, 2H),7.16-7.09 (m, 2H), 6.95 (d, J=8.4, 1H), 6.88 (dd, J=8.4, 2.0, 1H),5.79-5.74 (br m, 1H), 3.76-3.68 (m, 1H), 3.33-3.25 (m, 1H), 3.05-2.95(m, 1H), 1.31 (d, J=7.0, 3H).

Example 2

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid

A. 2-Amino-3-(3,4-dichloro-phenyl)-propionic acid methyl esterhydrochloride. To a stirred solution of(S)-2-tert-butoxycarbonylamino-3-(3,4-dichloro-phenyl)-propionic acid(0.67 g, 2.00 mmol) in MeOH (13 mL) at 0° C. was added SOCl₂ (0.29 mL,4.00 mmol). The reaction mixture was allowed to stir and warm to rtovernight. The mixture was concentrated to provide the product as awhite solid (0.56 g, 99%). ¹H NMR (400 MHz, DMSO-d₆): 8.66 (br s, 2H),7.65-7.60 (m, 2H), 7.26dd, J=8.2, 1.9, 1H), 4.37 (br s, 1H), 3.72 (s,3H), 3.18-3.14 (m, 2H).

B. (S)-2-2-Amino-4-iodo-benzoylamino)-3-(3,4-dichloro-phenyl)-propionicacid methyl ester. A solution of 4-iodo-2-nitrobenzoic acid (0.35 g,1.20 mmol) dissolved in SOCl₂ (5 mL) was heated at reflux for 2 h. Themixture was concentrated and the resulting liquid was dissolved in DMF(5 mL). DMAP (161 mg, 1.32 mmol) and2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl esterhydrochloride (0.37 g, 1.32 mmol) were added and the solution wasstirred overnight at rt. The mixture was poured into water and extractedwith EtOAc (3×). The organic layers were combined, dried (MgSO₄), andconcentrated to provide the crude product as a yellow oil. The oil waspurified by flash chromatography (hexanes/EtOAc) to provide the productas a colorless oil (50%, 313 mg). ¹H NMR (400 MHz, CDCl₃): 7.59 (d,J=8.1, 2H), 7.37(d, J=8.2, 1H), 7.28 (d, J=2.0, 1H), 7.18 (d, J=8.0,1H), 7.04 (dd, J=8.2, 2.0, 1H), 6.49 (d, J=7.4, 1H), 5.10-5.04 (m, 1H),3.81 (s, 3H), 3.33-3.17 (m, 2H).

C. (S)-2-(2-Amino-4-iodo-benzoylamino)-3-(3,4-dichloro-phenyl)-propionicacid methyl ester.(S)-2-(2-Amino-4-iodo-benzoylamino)-3-(3,4-dichloro-phenyl)-propionicacid methyl ester (313 mg, 0.60 mmol) was dissolved in 1:1 EtOAc/DCM (6mL) and SnCl₂.2H₂O (0.68 g, 2.99 mmol) was added. The mixture wasstirred overnight at rt and then satd. aq. NaHCO₃ was added (10 mL). Themixture was filtered through a pad of diatomaceous earth and rinsed withcopious water and DCM. The organic layer was separated, dried (MgSO₄),and concentrated to provide the desired product as a colorless oil (187mg, 63%). MS (ESI−): mass calcd. for C₁₇H₁₅Cl₂IN₂O₃, 493.1; m/z found,492 [M−H]⁻, 531 [M+K]⁻. ¹H NMR (400 MHz, CDCl₃): 7.36 (d, J=8.2, 1H),7.22 (d, J=1.9, 1H), 7.09-7.07 (m, 1H), 6.99-6.94 (m, 3H), 6.48 (d,J=7.1, 1H), 4.98 (q, J=5.6, 1H), 3.80(s, 3H), 3.25-3.11 (m, 2H).

D.(S)-2-[2-4Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid methyl ester. To a solution of(S)-2-(2-amino-4-iodo-benzoylamino)-3-(3,4-dichloro-phenyl)-propionicacid methyl ester (39 mg, 0.079 mmol) in DCM (1 mL) was added4-chlorosulfonyl-2,1,3-benzothiadiazole (37 mg, 0.158 mmol) and pyridine(30 μL, 0.371 mmol). The mixture was-shaken overnight at rt, thenpolymer bound tris(2-aminoethyl)amine resin was added. The resultingmixture was shaken for 2 h, and the resin was removed by filtration andrinsed with DCM. TBD methyl polystyrene resin was then added and themixture was shaken for 2 h. The liquid was drained and the resin waswashed with DCM (3×). A solution of 10% TFA in DCM (3 mL) was added tothe resin and the mixture was shaken for 1.5 h. The resin was removed byfiltration, washed with 10% TFA in DCM and the filtrate was concentratedto provide the desired product as a white solid (55 mg, 99%). ¹H NMR(400 MHz, CDCl₃): 11.10 (s, 1H), 8.36 (dd, J=7.0, 0.8, 1H), 8.24 (dd,J=8.8, 0.8, 1H), 8.02 (d, J=1.5, 1H), 7.75 (dd, J=8.8, 7.1, 1H),7.37-7.32 (m, 2H), 7.16 (d, J=2.0, 1H), 6.96 (d, J=8.3, 1H), 6.92 (dd,J=8.2, 2.0, 1H), 6.67 (d, J=7.3, 1H), 4.96 (q, J=5.7, 1H), 3.83 (s, 3H),3.20-3.12 (m, 2H).

E.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid. To(S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid methyl ester (55 mg, 0.079 mmol) in 2:1 water/THF (3 mL) was addedLiOH.2H₂O (7 mg, 0.158 mmol). The yellow solution was stirred for 2 hand then 20% aq. HCl (2 mL) was added. The mixture was extracted withEtOAc (3×). The organic layers were combined, dried (MgSO₄), andconcentrated to provide the desired product as a white solid (41 mg,76%). HPLC: R_(T)=9.77 min. MS (ESI−): mass calcd. for C₂₂H₁₅Cl₂IN₄O₅S₂,677.3; m/z found, 676 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.22 (s, 1H),8.33 (d, J=7.0, 1H), 8.12 (d, J=8.8, 1H), 7.98 (d, J=0.8, 1H), 7.70 (dd,J=8.6, 7.3, 1H), 7.33 (d, J=8.2, 1H), 7.22 (d, J=8.2, 1H), 7.02 (dd,J=8.2, 1.6, 1H), 6.93 (d, J=8.3, 1H), 6.73 (d, J=7.3, 1H), 4.99 (q,J=6.3, 1H), 3.31 (dd, J=14.2, 5.7, 1H), 3.20 (dd, J=14.2, 5.7).

Example 3

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-phenyl-propionicacid

A. 4,5-Dichlorophthalic acid monomethyl ester. To a stirred-suspensionof 4,5-dichlorophthalic anhydride (15.0 g, 69.1 mmol) in MeOH (1 L) wasadded NaOMe (5.40 g, 100 mmol). The mixture was heated at reflux for 12h. The mixture was cooled to rt and concentrated to a volume of ˜100 mL,and then was poured into 0.5 N HCl (1 L) causing precipitation of theproduct. The resulting white powder was collected by suction filtration,washed with water, and dried under vacuum to give 17.1 g (99.5%) of themonomethyl ester. ¹H NMR (400 MHz, CDCl₃): 8.02 (s, 1H), 7.84 (s, 1H),3.94 (s, 3H).

B. Methyl 2-amino-4,5-dichlorobenzoate. A suspension of4,5-dichlorophthalic acid monomethyl ester (17 g, 69 mmol) in SOCl₂ (100mL) was heated at reflux for 1 h. The resulting mixture was cooled andconcentrated to give a yellow oil. The oil was azeotroped with toluene(5×5 mL), leaving the acid chloride as a yellow liquid. ¹H NMR (400 MHz,CDCl₃): 7.96 (s, 1H), 7.82 (s, 1H), 3.95 (s, 3H). The crude acidchloride was stirred in dry acetone (400 mL) at 0° C. as a solution ofNaN₃ (18.0 g, 277 mmol) in water (120 mL) was added dropwise,maintaining the temperature below 10° C. After addition was complete,the orange reaction mixture was stirred 1 h at 0° C. The mixture wasconcentrated with no external heating. The residue was partitionedbetween water and DCM (3×). The combined organic layers were dried(Na₂SO₄) and concentrated to give the crude acyl azide as a tan solid.¹H NMR indicated the acyl azide methyl ester was contaminated with 3other minor unidentified components. ¹H NMR (400 MHz, CDCl₃): 7.87 (s,1H), 7.78 (s, 1H), 3.94 (s, 3H). The crude tan solid was suspended in amixture of acetic acid (240 mL) and water (120 mL) and heated at refluxfor 1 h. Rapid gas evolution occurred. The suspension was concentrated,and the resulting solid was collected by suction filtration and washedwith water. The crude solid was stirred in toluene and filtered. Thefiltrate was concentrated to a white solid (9.10 g, ˜54%, 91% pure by ¹HNMR). The aminobenzoate was used without further purification. ¹H NMR(400 MHz, CDCl₃): 7.92 (s, 1H), 6.78 (s, 1H), 5.77 (br s, 2H), 3.87 (s,3H).

C. 2-Amino-4,5-dichloro-benzoic acid. Methyl2-amino-4,5-dichlorobenzoate (2.1 g, 9.41 mmol) was dissolved in THF (15mL) and water (30 mL) was added. LiOH (0.79 g, 18.8 mmol) was added themixture was stirred overnight at rt. The product was precipitated byaddition of 10% aq. HCl (30 mL) and isolated by suction filtration. Thewhite solid was dried under vacuum (1.6 g, 81%). ¹H NMR (400 MHz,DMSO-d₆): 7.78 (s, 1H), 7.01 (s, 1H).

D. 3,4-Dichloroisatoic anhydride. 2-Amino-4,5-dichloro-benzoic acid (1.5g, 7.28 mmol) was dissolved in 1:1 DCM/THF (20 mL) and cooled to 0° C..Phosgene (20% in toluene, 5.4 mL, 8.00 mmol) and Hünig's base (2.54 mL,14.6 mmol) were added and the reaction was stirred overnight and warmedslowly to rt. The mixture was poured into water and extracted with DCM(3×) and EtOAc (2×). The combined organic layers were dried (MgSO₄), andconcentrated to provide the product as a white solid (1.6 g, 92%). HPLC:R_(T)=8.10 min. MS (ESI−): mass calcd. for C₈H₃Cl₂NO₃, 232.0; m/z found,231 [M−H]⁻. ¹H NMR (400 MHz, DMSO-d₆): 11.95 (s, 1H), 8.10 (s, 1H), 7.32(s, 1H).

E. 2-(2-Amino-4,5-dichloro-benzoylamino)-3-phenyl-propionic acid methylester. 3,4-Dichloroisatoic anhydride (147 mg, 0.634 mmol) was dissolvedin DMF (2 mL). (L)-Phenylalanine methyl ester hydrochloride (150 mg,0.697 mmol) and DMAP (85 mg, 0.697 mmol) were added and the mixture wasstirred overnight at rt. The mixture was quenched with water andextracted with EtOAc (3×). The combined organic layers were washed withwater, dried (MgSO₄), filtered and concentrated to provide the crudeproduct. The crude solid was purified by flash chromatography(hexanes/EtOAc) to provide the desired product as a white solid (150 mg,68%). ¹H NMR (400 MHz, CDCl₃): 7.27-7.21 (m, 5H), 7.07-7.05 (m, 2H),6.30 (d, J=7.2, 1H), 5.44 (br s, 2H), 4.95-4.90 (m, 1H), 3.71 (s, 3H),3.22-3.09 (m, 2H).

F.2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-phenyl-propionicacid. This compound was prepared from2-(2-amino-4,5-dichloro-benzoylamino)-3-phenyl-propionic acid methylester and benzo[1,2,5]thiadiazole-4-sulfonyl chloride as in EXAMPLE 2,Parts D and E. HPLC: R_(T)=10.10 min. MS (ESI−): mass calcd. forC₂₂H₁₆Cl₂N₄O₅S₂, 551.4; m/z found, 550 [M−H]. ¹H NMR (400 MHz, CDCl₃):11.11 (s, 1H), 8.33 (dd, J=7.1, 0.9, 1H), 8.20 (dd, J=8.8, 0.8, 1H),7.83 (s, 1H), 7.70 (dd, J=8.8, 7.1, 1H), 7.28 (m, 3H), 7.20 (s, 1H),7.13 (dd, J=7.4, 1.7, 2H), 6.42 (d, J=7.5, 1H), 5.00 (dd, J=13.3, 6.0,1H), 3.32 (dd, J=14.1, 5.7, 1H), 3.23 (dd, J=14.1, 6.1, 1H).

Example 4

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-phenyl)-propionicacid

A. (1R,2R)-Pseudoephedrine glycinamide hydrate. To a flame-driedthree-necked round bottom flask was added (1R,2R)-(−)-pseudoephedrine(1,0 g, 60.5 mmol), glycine methyl ester hydrochloride (9.9 g, 78.7mmol), and THF (90 mL). The mixture was stirred for 15 min at rt andlithium t-butoxide (6.8 g, 84.7 mmol) was added. The resultingsuspension was stirred at rt for 3 h. Water (150 mL) was added and theTHF was removed in vacuo. The aqueous phase was extracted with DCM (3×).The combined organic layers were dried (K₂CO₃), filtered, andconcentrated. Hot THF (50 mL) was added to dissolve the residue andwater (2 mL) was added. The mixture was allowed to stand overnight. Awhite solid formed and was collected by suction filtration. The productwas washed with Et₂O and dried (10.2 g, 70%). ¹H NMR (400 MHz, CDCl₃;1:1 ratio of rotamers): 7.42-7.28 (m, 5H), 4.65-4.52 (m, 1.5H),3.95-3.83 (m, 0.5H), 3.71 (d, J=15.6, 0.5H), 3,45 (d, J=16.9, 1H), 3.37(d, J=17.0, 0.5H), 2.97 (s, 1.5H), 2.79 (s, 1.5H), 1.85 (br s, 3H), 1.09(d, J=6.8, 1.5H), 0.99 (d, J=6.8, 1.5H).

B.2-Amino-3-(3-bromo-phenyl)-N-((2R)-hydroxy-(1R)-methyl-2-phenyl-ethyl)-N-methyl-propionamide.A flame-dried flask was charged with LiCl (100 mg, 2.44 mmol). The flaskwas flushed with N₂ and (1R,2R)-pseudoephedrine glycinamide hydrate (1.0g, 4.17 mmol) was added. The solid reagents were dissolved in THF (20mL), cooled to 0° C., and lithium bis(trimethylsilyl)amide (LHMDS; 1 Min THF, 13.3 mL, 13.3 mmol) was added. The bright yellow solution wasstirred for 1 h and then 3-bromobenzyl bromide (1.25, 5.00 mmol) wasadded. The mixture was stirred for 2 h at 0° C. and 1 M HCl (200 mL) wasadded. The solution was extracted with EtOAc (3×). The organic layerswere combined and washed with 1 M HCl (3×). All aqueous layers werecombined, cooled to 0° C., and basified to pH 14 with 40% aq. NaOH. Theaqueous layers were extracted with DCM (4×). The organic layers werecombined, dried (K₂CO₃), filtered and concentrated to provide the crudeproduct. The crude product was purified by flash chromatography(DCM/MeOH) to provide the product as a colorless oil (232 mg, 14%). ¹HNMR (400 MHz, CDCl₃): 8.39 (br s, 1H), 8.17 (br s, 2H), 7.30-7.16 (m,7H), 7.08-6.97 (m, 2H), 4.88-4.81 (m, 1H), 4.39-4.36 (m, 1H), 4.25 (d,J=9.7, 1H), 3.16-3.13 (m, 1H), 2.96-2.89 (m, 1H), 2.16 (s, 3H), 0.48 (d,J=6.9, 3H).

C. (S)-3-(3-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid. Asuspension of2-amino-3-(3-bromo-phenyl)-N-((2R)-hydroxy-(1R)-methyl-2-phenyl-ethyl)-N-methyl-propionamide(232 mg, 0.593 mmol) in 1 M NaOH (1.2 mL) and water (1.2 mL) was heatedat reflux for 2 h and then cooled to rt, whereupon the clear solutionbecame cloudy. Water (10 mL) was added and the solution was extractedwith DCM (2×). The combined organic layers were washed with water. Theaqueous layers were back-extracted with DCM, then combined andconcentrated to 5 mL. NaHCO₃ (100 mg, 1.19 mmol) and dioxane (10 mL)were added. The mixture was cooled to 0° C. and di-tert-butyldicarbonate (0.24 mL, 1.02 mmol) was added. The reaction mixture wasstirred overnight and allowed to warm to rt. Water (20 mL) was added andthe solution was extracted with EtOAc (3×). The organic layers werecombined and washed with 2% aq. NaHCO₃. The combined aqueous layers wereacidified to pH 3.5 with satd. aq. citric acid and extracted with EtOAc(3×). The organic layers were combined, washed with water, dried(Na₂SO₄), and concentrated to provide the product as a clear, colorlessoil (38 mg, 17%). ¹H NMR (400 MHz, CDCl₃; 1.7:1 ratio of rotamers):7.40-7.33 (m, 3.2H), 7.12-7.20 (m, 3.2H), 6.69 (d, J=6.8, 0.6H), 5.00(d, J=7.8, 1H), 4.62-4.54 (m, 1H), 4.48-4.34 (m, 0.6H), 3.26-3.12 (m,1.6H), 3.10-2.84 (m, 1.6H), 1.43 (s, 9H), 1.29 (s, 5.4H).

D. (S)-2-Amino-3-(3-bromo-phenyl)-propionic acid methyl esterhydrochloride.(S)-3-(3-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid wastreated as in EXAMPLE 2, Part A, to provide a white solid. MS (ESI+):mass calcd. for C₁₀H₁₂BrNO₂, 258.1; m/z found, 259 [M+H]⁺.

E.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-phenyl)-propionicacid. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acidwas coupled to (S)-2-amino-3-(3-bromo-phenyl)-propionic acid methylester hydrochloride as in EXAMPLE 1, Part C. The methyl ester washydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC:R_(T)=9.91 min. MS (ESI−): mass calcd. for C₂₂H₁₆BrIN₄O₅S₂, 687.3; m/zfound, 686 [M−H]⁻. ¹H NMR (400 MHz, DMSO-d₆): 13.05 (s, 1H), 11.77 (s,1H), 9.03 (d, J=7.8, 1H), 8.45-8.35 (m, 2H), 7.92-7.86 (m, 1H), 7.82 (d,J=1.5, 1H), 7.53-7.51 (br m, 1H), 7.47-7.38 (m, 2H), 7.36-7.34 (m, 1H),7.31-7.19 (m, 2H), 4.65-4.54 (m, 1H), 3.19 (dd, J=14.0, 4.7, 1H), 3.00(dd, J=13.7, 10.8, 1H).

Example 5

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide

A. 2-(3,4-Dichloro-phenyl)-propionitrile. To a −78° C. solution of(3,4-dichloro-phenyl)-acetonitrile (5.0 g, 26.9 mmol) in THF (60 mL) wasadded LHMDS (1 M in THF, 28.2 mL, 28.2 mmol). The reddish orangesolution was stirred at −78° C. for 1 h and Mel (1.76 mL, 28.2 mmol) wasadded. The mixture was allowed to warm to rt overnight. The mixture wasdiluted with 1 M HCl (20 mL) and extracted with Et₂O (3×). The combinedorganic layers were dried (MgSO₄) and concentrated to provide a darkbrown oil. The crude product was purified by flash chromatography(hexanes/EtOAc) to provide a colorless oil (5.0 g, 93%). ¹H NMR (400MHz, CDCl₃): 7.52-7.42 (m, 2H), 7.25-7.18 (m, 1H), 3.88 (q, J=7.3, 1H),1.64 (d, J=7.3, 3H).

B. 2-(3,4-Dichloro-phenyl)-propylamine hydrochloride.2-(3,4-Dichloro-phenyl)-propionitrile (5.0 g, 25.0 mmol) was dissolvedin THF (80 mL). BH₃.THF (1 M in THF, 27.5 mL, 27.5 mmol) was added andthe mixture was stirred overnight at rt. EtOH (10 mL) was added, themixture was stirred for 20 min, and HCl in Et₂O (2 M, 12.5 mL) wasadded. After stirring for 1 h, water was added, causing precipitation ofthe product. The product was collected by suction filtration and dried(4.2 g, 70%). MS (ESI+): mass calcd. for C₉H₁₁Cl₂N, 204.1; m/z found,205 [M+H]+⁺. ¹H NMR (400 MHz, CD₃OD): 7.45-7.42 (m, 2H), 7.17-7.15 (m,1H), 3.05-3.02 (m, 2H), 2.98-2.96 (m, 1H), 1.24 (d, J=6.5, 3H).

C. 2-Amino-4-bromo-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide. Thetitle compound (68 mg, 27%) was prepared from 4-bromo-2-nitrobenzoicacid as in Example 2, Parts B and C. MS (ESI−): mass calcd. forC₁₆H₁₅BrCl₂N₂O, 402.1; m/z found, 401 [M−H]⁻, 440 [M+K]⁻. ⁻H NMR (400MHz, CDCl₃): 7.39 (d, J=8.2, 1H), 7.33 (d, J=2.0, 1H), 7.07 (dd, J=8.3,2.0, 1H), 6.95 (d, J=8.4, 1H), 6.82 (d, J=1.8, 1H), 6.69 (dd, J=8.4,1.9, 1H), 5.98-5.96 (br m, 1H), 5.58 (br s, 2H), 3.70-3.65 (m, 1H),3.38-3.31 (m, 1H), 3.04 (sext, J=6.8, 1H), 1.30 (d, J=7.0, 3H).

D.2-(Benzo[1,5]thiadiazole-4-sulfonylamino)-4-bromo-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide.The title compound (45 mg, 99%) was prepared as in Example 2, Part D.HPLC: R_(T)=11.06 min. MS (ESI−): mass calcd. for C₂₂H₁₇BrCl₂N₄O₃S₂,600.3; m/z found, 599 [M−H]⁻. ¹H NMR(400 MHz, CDCl₃): 11.47 (s, 1H),8.36 (dd, J=7.0, 0.9, 1H), 8.23 (dd, J=8.8, 0.9, 1H), 7.86 (d, J=1.8,1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.40 (d, J=8.2, 1H), 7.29 (d, J=2.0,1H), 7.05 (ddd, J=7.6, 5.6, 2.0, 2H), 6.93 (d, J=8.4, 1H), 5.85 (br m,1H), 3.68 (td, J=13.2, 6.4, 1H), 3.31 (ddd, J=13.8, 8.7, 5.4, 1H), 3.00(m, 1H), 1.31 (d, J=7.0, 3H).

Example 6

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2,2-bis-(4-chloro-phenyl)-ethyl]-4-chloro-benzamide

A. 2,2-Bis-(4-chloro-phenyl)-acetamide. A suspension of2,2-bis-(4-chloro-phenyl)-acetic acid (0.50 g, 1.8 mmol) in SOCl₂ (5 ML)was heated at reflux for 1 h. The mixture was concentrated, and theresidue was azeotroped with toluene (3×). The crude acid chloride wasstirred in DCM (10 mL) at rt and treated with NH₃ (0.5 M in dioxane, 14mL, 7.5 mmol). After 1 h, the reaction mixture was concentrated, and theresidue was diluted with satd. aq. NaHCO₃ and extracted with DCM (3×).The combined organics were dried (Na₂SO₄) and concentrated to providethe amide as a white solid (0.50 g, 100%). The amide was used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃): 7.35-7.28 (m, 4H),7.23-7.17 (m, 4H), 5.69 (br s, 1H), 5.53 (br s, 1H), 4.87 (s, 1H).

B. 2.2-Bis-(4-chloro-phenyl)-ethylamine. To a solution of2,2-bis-(4-chloro-phenyl)-acetamide (0.50 g, 1.8 mmol) in THF (10 mL) atrt was added BH₃.THF (1.0 M in THF, 4.5 mL, 4.5 mmol). The solution washeated at reflux for 2 h. The mixture was-cooled in an ice bath, and theexcess BH₃ was quenched by careful addition of 10 mL of MeOH. HCl (2.0 Min MeOH, 5 mL) was added, and the resulting mixture was heated at refluxfor 1 h. After cooling, the mixture was concentrated, and the residuewas partitioned between 1 N HCl and Et₂O. The acidic aqueous layer wasbasified with 10 N NaOH and extracted with Et₂O (3×). The combinedorganic extracts were dried (MgSO₄) and concentrated to provide thedesired amine (181 mg, 38%). The amine was used without furtherpurification. ¹H NMR (400 MHz, CDCl₃): 7.30-7.264 (m, 4H), 7.18-7.12 (m,4H), 3.94 (t, J=7.5, 1H), 3.28 (d, J=7.6, 2H), 1.06 (br s, 2H).

C.2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2,2-bis-(4-chloro-phenyl)-ethyl]-4-chloro-benzamide.2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid wascoupled with 2,2-bis-4-chloro-phenyl)-ethylamine as in EXAMPLE 1, PartC. HPLC: R_(T)=11.40 min. MS (ESI−): mass calcd. for C₂₇H₁₉Cl₃N₄O₃S₂,616.00; m/z found, 615/617 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.49 (s,1H), 8.36 (dd, J=7.1, 1.0, 1H), 8.23 (dd, J=8.8, 1.0, 1H), 7.72 (dd,J=8.8, 7.0, 1H), 7.68 (d, J=1.8, 1H), 7.34-7.30 (m, 4H), 7.18-7.13 (m,4H), 6.89 (d, J=8.4, 1H), 6.86 (dd, J=8.4, 1.8, 1H), 5.87 (br t, J=5.6,1H), 4.24 (t, J=8.0, 1H), 3.95 (dd, J=7.9, 5.9, 2H).

Example 7

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(4-chloro-phenyl)-2-methyl-propyl]-benzamide

A. 2-(4-Chloro-phenyl)-isobutyramide. Prepared from2-(4-chloro-phenyl)-2-methyl-propionic acid (0.50 g, 2.5 mmol), as inEXAMPLE 6, Step A (0.45 g, 92%). ¹H NMR (400 MHz, CDCl₃): 7.34 (s, 4H),5.26 (br s, 1H), 5.15 (br s, 1H), 1.57 (s 6H).

B. 2-(4-Chloro-phenyl)-2-methyl-propylamine. Prepared from2-(4-chloro-phenyl)-isobutyramide (0.45 g, 2.3 mmol), as in EXAMPLE 6,Step B (310 mg, 73%). ¹H NMR (400 MHz, CDCl₃): 7.32-7.24 (m, 4H), 2.78(s, 2H), 1.29 (s, 6H), 0.97 (br s, 2H).

C.2-(Benzo[2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(4-chloro-phenyl)-2-methyl-propyl]-benzamide.2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid wascoupled with 2-(4-chloro-phenyl)-2-methyl-propylamine as in EXAMPLE 1,Part C. HPLC: R_(T)=11.08 min. MS (ESI−): mass calcd. forC₂₃H₂₀Cl₂N₄O₃S₂, 534.04; m/z found, 533/535 [M−H]⁻. ¹H NMR (400 MHz,CDCl₃): 11.53 (s, 1H), 8.35 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0,1H), 7.71 (dd, J=8.8, 7.0, 1H), 7.70 (d, J=1.8, 1H), 7.35-7.31 (m, 2H),7.30-7.26 (m, 2H), 6.89 (d, J=8.3 1H), 6.86 (dd, J=8.4, 1.8, 1H),5.58-5.52 (m, 1H), 3.56 (d, J=6.1, 2H), 1.36 (s, 6H).

Example 8

(S)-3-(5-Bromo-thiophen-2-yl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester

A. Diethylthiocarbamic acid O-quinoxalin-5-yl ester. A mixture of5-hydroxyquinoxaline (2.13 g, 14.6 mmol), finely ground K₂CO₃ (4.0 g, 29mmol), and DMF (50 mL) was stirred at 23° C. for 1 h. Soliddiethylthiocarbamoyl chloride (2.439 g, 16.1 mmol) was then added. Theresulting mixture was stirred for 2 h, then was diluted with water (150mL) and extracted with Et₂O (2×100 mL). The combined organic extractswere washed with water (100 mL) and brine (100 mL), then dried andconcentrated to a viscous orange oil, which was used withoutpurification (3.63 g, 95%). MS (ESI+): mass calcd. for C₁₃H₁₅N₃OS,261.1; m/z found, 262 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.85-8.65 (m,2H), 7.96 (dd, J=8.5, 1.1, 1H), 7.71 (t, J=7.9, 1H), 7.46 (dd, J=7.6,1.2, 1H), 3.87 (q, J=7.1, 2H), 3.78 (q, J=7.1, 2H), 1.38 (t, J=7.1, 3H),1.28 (t, J=7.1, 3H). ¹³C NMR (125 MHz, CDCl₃): 186.6, 149.4, 144.9,144.5, 143.4, 137.0, 128.9, 127.0, 123.1, 48.2, 44.5, 13.1, 11.5.

B. Diethylthiocarbamic acid S-quinoxalin-5-yl ester. Neatdiethylthiocarbamic acid O-quinoxalin-5-yl ester (0.52 g, 2.0 mmol) washeated at 240° C. for 1 h. The resulting brown oil was chromatographed(EtOAc/hexanes), providing a pale yellow oil (0.49 g, 94%). MS (ESI+):mass calcd. for C₁₃H₁₅N₃OS, 261.1; m/z found, 262 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 8.93 (d, J=1.8, 1H), 8.87 (d, J=1.8, 1H), 8.18 (dd, J=8.4,1.2, 1H), 8.13 (dd, J=7.3, 1.2, 1H), 7.81 (dd, J=7.3, 1.0, 1H), 3.61 (brs, 2H), 3.43 (br s, 2H), 1.38. (br s, 3H), 1.16 (br s, 3H).

C. Quinoxaline-5-sulfonyl chloride. A solution of diethylthiocarbamicacid S-quinoxalin-5-yl ester (3.20 g, 12.3 mmol), KOH (6.89 g, 123 mmol)and MeOH (100 mL) was heated at reflux for 16 h. The solution wasallowed to cool to rt, and then acetic acid (7 mL) was added. Themixture was diluted with water (100 mL) and extracted with EtOAc (2×100mL). The combined extracts were washed with water (100 mL) and brine(100 mL), then dried and concentrated to a tan solid (1.90 g). A portionof this thiol (0.22 g, 1.4 mmol) was combined with DCM (50 mL), formicacid (25 mL), and water (25 mL), and the resulting biphasic mixture wascooled to 0° C. Chlorine gas was bubbled through this mixture with rapidstirring for 5 min. The mixture was transferred to a separatory funnel,and the organic phase was collected. The aqueous phase was extractedwith DCM (50 mL), and the combined organic phases were washed with 1 MNaOH (50 mL) and brine (50 mL), and then dried. The solution wasconcentrated to afford the title compound as a light yellow crystallinesolid (0.28 g, 86%). ¹H NMR (500 MHz, CDCl₃): 9.17 (d, J=1.8, 1H), 9.07(d, J=1.8, 1H), 8.60 (dd, J=7.5, 1.4, 1H), 8.53 (dd, J=8.4, 1.4, 1H),7.96 (dd, J=8.6, 0.8, 1H). ¹³C NMR (125 MHz, CDCl₃): 146.9, 146.8,143.7, 140.4, 139.0, 138.4, 132.4, 128.8.

D. 4-Chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid methyl ester. Asolution of methyl 2-amino-4-chlorobenzoate (0.33 g, 1.8 mmol),quinoxaline-5-sulfonyl chloride (0.40 g, 1.8 mmol), pyridine (0.71 mL,8.8 mmol), and DCM (10 mL) was stirred at rt for 16 h. EtOAc (75 mL) wasadded and the solution was washed with satd. aq. NaHCO₃ (50 mL), thendried and concentrated. Chromatographic purification of this residue(EtOAc/hexanes) gave the title compound as a white solid (0.60 mg, 90%).MS (ESI+): mass. calcd. for C₁₆H₁₂ClN₃O₄S, 377.0; m/z found, 378 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 11.44 (s, 1H), 8.97 (d, J=1.8, 1H), 8.95 (d,J=1.8, 1H), 8.61 (dd, J=7.4, 1.4, 1H), 8.33 (dd, J=8.5, 1.4, 1H), 7.89(dd, J=8.4, 1.0, 1H), 7.84 (d, J=2.0, 1H), 7.77 (d, J=8.6, 1H), 6.89(dd, J=8.6, 2.0, 1H), 3.90 (s, 3H).

E. 4-Chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid. A solution ofLiOH.H₂O (0.32 g, 7.7 mmol) in water (5 mL) was added to a solution of4-chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid methyl ester (0.58g, 1.5 mmol) and THF (10 mL). The biphasic mixture was stirred rapidlyat rt for 1.6 h, then adjusted to pH 5 with 1 M HCl. The resultingprecipitate was collected by filtration to afford the acid as a whitesolid (0.51 g, 92%). MS (ESI+): calcd. for C₁₅H₁₀ClN₃O₄S, 363.0; m/zfound, 364 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 14.20 (br s, 1H), 11.73(s, 1H), 9.12 (d, J=1.6, 1H), 9.00 (d, J=1.5, 1H), 8.65 (d, J=7.3, 1H),8.42 (d, J=8.3, 1H), 8.06 (t, J=7.8, 1H), 7.80 (d, J=8.5, 1H), 7.63 (d,J=2.0, 1H), 7.07 (dd, J=8.4, 1.9, 1H).

F. (S)-2-Amino-3-(5-bromo-thiophen-2-yl)-propionic acid methyl esterhydrochloride.(S)-2-tert-Butoxycarbonylamino)-3-(5-bromo-thiophen-2-yl)-propionic acidwas treated as in EXAMPLE 2, Part A. ¹H NMR (400 MHz, CD₃OD): 7.02 (d,J=3.6, 1H), 6.79 (d, J=3.6, 1H), 4.35 (t, J=5.9, 1H), 3.87 (s, 3H), 3,42(d, J=5.7, 2H).

G.(S)-3-(5-Bromo-thiophen-2-yl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester. 4-Chloro-2-(quinoxaline-5-sulfonylamino)benzoic acidwas coupled with (S)-2-amino-3-(5-bromo-thiophen-2-yl)-propionic acidmethyl ester hydrochloride as in EXAMPLE 1, Part C. HPLC: R_(T)=10.34min. MS (ESI−): mass calcd. for C₂₃H₁₈BrClN₄O₅S₂, 607.96; m/z found,607/609 [M−H]⁻. ⁻H NMR (500 MHz, CDCl₃): 11.31 (s, 1H), 8.94 (d, J=1.8,1H), 8.91 (d, J=1.8, 1H), 8.59 (dd, J=7.4, 1.4, 1H), 8.32 (dd, J=8.4,1.3, 1H), 7.89 (dd, J=8.4, 7.4, 1H), 7.80 (d, J=2.0, 1H), 7.27 (d,J=8.4, 1H), 6.96.(dd, J=8.4, 2.0, 1H), 6.86 (d, J=3.7, 1H), 6.57 (br d,J=6.8, 1H), 6.48 (d, J=3.6, 1H), 4.92 (dt, J=7.0, 4.6, 1H), 3.83 (s,3H), 3.40 (d, J=4.6, 2H).

Example 9

(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-naphthalen-2-yl-propionicacid

A. (S)-2-Amino-3-naphthalen-2-yl-propionic acid methyl esterhydrochloride.(S)-2-(tert-Butoxycarbonylamino)-3-naphthalen-2-yl-propionic acid wastreated as in EXAMPLE 2, Part A, to give a white solid. ¹H NMR (400 MHz,CD₃OD): 7.91-7.82 (m, 3H), 7.75 (br s, 1H), 7.54-7.47 (m, 2H), 7.38 (ddJ=8.4, 1.7, 1H), 4.43 (dd, J=7.7, 6.0, 1H), 3.82 (s, 3H), 3.45 (dd,J=14.4, 5.9, 1H), 3.32 (dd, J=14.4, 7.7, 1H).

B.(S)-3-Naphthalen-2-yl-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester. 4-Chloro-2-(quinoxaline-5-sulfonylamino)benzoic acidwas coupled with (S)-2-amino-3-naphthalen-2-yl-propionic acid methylester hydrochloride as in EXAMPLE 1, Part C.

C.(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-naphthalen-2-yl-propionicacid.(S)-3-Naphthalen-2-yl-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to provide thetitle acid as a solid. HPLC: R_(T)=9.60 min. MS (ESI−): mass calcd. forC₂₈H₂₁ClN₄O₅S, 560.09; m/z found, 559 [M−H]⁻. ⁻H NMR (400 MHz, CD₃OD):8.66 (d, J=1.8, 1H), 8.58 (d, J=1.7, 1H), 8.51 (dd, J=7.4, 1.3, 1H),8.26 (dd, J=8.5, 1.3, 1H), 7.90 (dd, J=8.4, 7.4, 1H), 7.85-7.73 (m, 3H),7.70 (br s, 1H), 7.67 (d, J=2.0 1H), 7.47-7.38 (m, 3H), 7.35 (d, J=8.5,1H), 6.89 (dd, J=8.5, 2.0, 1H), 4.97-4.85 (m, 1H), 3,46 (dd, J=13.9,4.8, 1H), 3.19 (dd, J=13.9, 9.8, 1H).

Example 10

(±)-4-Chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-2-(2,4-difluoro-benzenesulfonylamino)-benzamide

A. 4-Chloro-2-(2,4-difluoro-benzenesulfonylamino)-benzoic acid methylester. To a solution of methyl 4-chloroanthranilate (0.50 g, 2.7 mmol)and pyridine (0.87 mL, 10.8 mmol) in DCM (10 mL) at rt was added2,4-difluorobenzenesulfonyl chloride (0.64 g, 3.0 mmol). The mixture wasstirred overnight at rt, poured into 1 N HCl, and extracted with DCM(3×). The combined organic extracts were dried (Na₂SO₄) andconcentrated. The residue was purified by flash chromatography(EtOAc/hexanes) to provide 0.69 g (70%) of the desired sulfonamide as asolid. ¹H NMR (400 MHz, CDCl₃): 11.02 (s, 1H), 8.07-8.00 (m, 1H), 7.91(d, J=8.6, 1H), 7.64 (d, J=2.0, 1H), 7.04-6.98 (m, 1H), 7.02 (dd, J=8.6,2.0, 1H), 6.93-6.86 (m, 1H), 3.94 (s, 3H).

B. 4-Chloro-2-(2,4-difluoro-benzenesulfonylamino)-benzoic acid. Thetitle compound (0.65 g, 98%) was prepared from4-chloro-2-(2,4-difluoro-benzenesulfonylarmino)-benzoic acid methylester as in Example 1, Part B. ¹H NMR (500 MHz, CD₃OD): 8.08-8.02 (m,1H), 7.98 (d, J=8.5, 1H), 7.60 (d, J=2.0, 1H), 7.20-7.14 (m, 2H), 7.10(dd, J=8.5, 2.1, 1H).

C.(±)-4-Chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-2-(2,4-difluorobenzenesulfonylamino)-benzamide.4-Chloro-2-(2,4-difluoro-benzenesulfonylamino)-benzoic acid was coupledwith (±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE1, Part C. HPLC: R_(T)=12.04 min. MS (ESI−): mass calcd. forC₂₂H₁₇Cl₃FN₂O₃S₂, 532.00; m/z found, 531/533 [M−H]⁻. ¹H NMR (400 MHz,CDCl₃): 11.41 (s, 1H), 8.00 (ddd, J=8.6, 8.6, 6.0, 1H), 7.61 (d, J=2.0,1H), 7.42 (d, J=8.2, 1H), 7.32 (d, J=2.1, 1H), 7.11 (d, J=8.4, 1H), 7.08(dd, J=8.2, 2.1, 1H), 7.03-6.97 (m, 1H), 6.97 (dd, J=8.4, 2.0, 1H),6.92-6.86 (m, 1H), 6.02-5.95 (br m, 1H), 3.76-3.68 (m, 1H), 3.41-3.31(m, 1H), 3.11-3.01 (m, 1H), 1.32 (d, J=7.0, 3H).

Example 11

(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[1-carbamoyl-2-(4-chloro-phenyl)-ethyl]-4,5-dichloro-benzamide

The title compound (3 mg, 20%) was prepared from(S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionicacid and NH₃ (0.5 M in dioxane) as in Example 1, Part C. HPLC:R_(T)=10.08 min. MS (ESI−): mass calcd. for C₂₂H₁₆Cl₃N₅O₄S₂, 582.97; m/zfound, 582/584 [M−H]⁻. ⁻H NMR (400 MHz, CDCl₃): 11.34 (s, 1H), 8.37 (dd,J=7.1, 1.0, 1H), 8.24 (dd, J=8.8, 1.0, 1H), 7.84 (s, 1H), 7.73 (dd,J=8.8, 7.1, 1H), 7.36 (s, 1H), 7.36-7.32 (m, 2H), 7.24-7.20 (m, 2H),6.84 (br d, J=6.9, 1H), 5.47 (br s, 1H), 5.41 (br s, 1H), 4.68 (ddd,J=8.6, 7.0, 5.0, 1H), 3.18 (dd, J=13.7, 4.9, 1H), 3.01 (dd, J=13.6, 8.6,1H).

Example 12

(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-1-hydroxymethyl-ethyl]-4-methyl-benzamide

A. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-methylbenzoic acidmethyl ester. The title compound (1.22 g, 53%) was prepared frombenzo[1,2,5]thiadiazole-4-sulfonyl chloride and 2-amino-4-methyl-benzoicacid methyl ester as in Example 10, Part A. ¹H NMR (500 MHz, CDCl₃):11.28 (s, 1H), 8.36 (dd, J=7.1, 1.0, 1H), 8.19 (dd, J=8.8, 1.0, 1H),7.73 (d, J=8.1, 1H), 7.68 (dd, J=8.8, 7.1, 1H), 7.51 (br s, 1H), 6.77

B. 2-(Benzo[1.2,5]thiadiazole-4-sulfonylamino)-4-methylbenzoic acid. Asolution of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-methylbenzoicacid methyl ester (1.22 g, 3.36 mmol) in 3:1 THF/water (10 mL) wastreated with LiOH.H₂O (1.41 g, 33.6 mmol) and was stirred at rt for 16h. The mixture was acidified with 1 N HCl, and the resulting precipitatewas collected by filtration, washing with water. Drying in air providedthe title acid as a tan solid (0.89 g, 2.5 mmol, 74%). ¹H NMR (500 MHz,CDCl₃): 11.16 (s, 1H), 8.38 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0,1H), 7.84 (d, J=8.1, 1H), 7.71 (dd, J=8.8, 7.1, 1H), 7.56 (br s, 1H),6.83 (br d, J=8.4, 1H), 2.32 (s, 3H).

C.(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-1-hydroxymethyl-ethyl]-4-methyl-benzamide.2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-methyl-benzoic acid wascoupled with (±)-2-amino-3-(4-chloro-phenyl)-propan-1-ol as in EXAMPLE1, Part C. HPLC: R_(T)=9.31 min. MS (ESI−): mass calcd. forC₂₃H₂₁ClN₄O₄S₂, 516.07; m/z found, 515 [M−H]⁻. ¹H NMR (400MHz, CDCl₃):11.52 (s, 1H), 8.33 (dd, J=7.0, 1.0, 1H), 8.19 (dd, J=8.8, 1.0, 1H),7.68 (dd, J=8.8, 7.0, 1H), 7.48 (s, 1H), 7.32-7.27 (m, 2H), 7.21-7.17(m, 2H), 7.09 (d, J=8.0, 1H), 6.75 (d, J=8.0, 1H), 6.28 (br d, J=7.4,1H), 4.32-4.23 (m, 1H), 3.72 (dd, J=10.8, 3.6, 1H), 3.65 (dd, J=10.8,4.5, 1H), 2.91 (d, J=7.4, 2H), 2.75 (br s, 1H), 2.27 (s, 3H).

Example 13

(S)-Benzo[1,2,5]thiadiazole-4-sulfonic acid[6-bromo-1,3-dioxo-2-(2-phenyl-propyl)-2,3-dihydro-1H-isoindol-4-yl]-amide

A. Methyl 4,5-dibromo-2-furoate. Neat methyl-2-furoate (20.0 g, 1,58mmol), in a 500 mL round bottom three-necked flask fitted with amechanical stirrer, was stirred as AlCl₃ (45.0 g, 337 mmol) wascarefully added in several portions. A mild exotherm was observed. Br₂(54.0 g, 338 mmol) was then added via dropping funnel over 30 min. Theresulting thick mixture was stirred for 30 min. The mixture was cooledin an ice bath and treated slowly with crushed ice. The resultingmixture was extracted with Et₂O (3×). The combined organic extracts werewashed with 10% aq. Na₂S₂O₃, dried (MgSO₄), and concentrated to give ayellow solid. The crude product was purified by flash chromatography(Et₂O/hexanes) to provide 26.19 g (58%) of the desired dibromofuroate asa pale yellow solid. ¹H NMR (400 MHz, CDCl₃): 7.18 (s, 1H), 3.90 (s,3H).

B. 4,5-Dibromo-2-furoic acid. To a suspension of methyl4,5-dibromo-2-furoate (26.19 g, 92.2 mmol) in THF (60 mL) at rt wasadded LiOH (3 M in water, 60 mL, 180 mmol). The biphasic mixture wasstirred for 4 h. The mixture was poured into 1 N HCl (500 mL) andextracted with DCM (3×). The combined organic layers were dried (Na₂SO₄)and concentrated to provide 24.59 g (99%) of the acid as an off-whitesolid. ¹H NMR (400 MHz, CD₃OD): 7.30 (s, 1H).

C. 4-Bromo-2-furoic acid. 4,5-Dibromo-2-furoic acid (24.51 g, 90.8 mmol)was dissolved in a mixture of water (280 mL) and aq. NH₄OH (33% NH₃; 80mL) and cooled in an ice bath. The mixture was stirred rapidly as zincdust (6.23 g, 95.3 mmol) was added in portions while keeping theinternal temperature below 7° C. The mixture was stirred at 0° C. for 30min. HPLC analysis of an aliquot of the reaction mixture indicated somestarting material remaining. An additional portion of zinc dust (0.5 g,7.6 mmol) was added and the mixture was stirred at 0° C. for 30 min.HPLC analysis of an aliquot indicated only a trace of starting materialas well as formation of a small amount of 2-furoic acid fromover-reduction. The mixture was acidified to pH 1 with conc. HCl causingprecipitation of the product. The mixture was cooled to 10° C., and theproduct was collected by suction filtration, washed with water, and airdried to provide 8.0 g (46%) of the desired acid. Additional productcould be obtained by extraction of the filtrate with DCM andrecrystallization of the crude extract from water. ¹H NMR (400 MHz,CDCl₃): 7.76 (d, J=0.8, 1H), 7.14 (d, J=0.8, 1H).

D. 4-Bromo-furan-2-carbonyl azide. A suspension of 4-bromo-2-furoic acid(1.87 g, 9.8 mmol) was heated at reflux in SOCl₂ (5 mL) for 1 h. Themixture was concentrated, and the residue was azeotroped with toluene(3×). The crude acid chloride was stirred in acetone (15 mL) at 0° C.,and a solution of NaN₃ (702 mg, 10.8 mmol) in water (5 mL) was addeddropwise via pipet. The mixture was stirred for 1 h at 0° C. then wasconcentrated without external heating. The residue was diluted withsatd. aq. NaHCO₃ and extracted with DCM (3×). The combined organiclayers were dried (Na₂SO₄) and concentrated without heating to give 1.85g (87%) of the acyl azide as a white solid. ¹H NMR (400 MHz, CDCl₃):7.65 (d, J=0.9, 1H), 7.26 (d, J=0.9, 1H).

E. (S)-E-3-(2-phenyl-propylcarbamoyl)-acrylic acid. To a solution ofmaleic anhydride (765 mg, 7.8 mmol) in acetic acid (20 mL) at rt wasadded (S)-2-phenylpropylamine. The mixture was stirred overnight thenwas partially concentrated. Water (50 mL) was added causingprecipitation of the product acid. The white solid was collected bysuction filtration, washed with water, and dried to provide 1.44 g (79%)of the pure acid. ¹H NMR (400 MHz, CDCl₃): 7.38-7.32 (m, 2H), 7.29-7.24(m, 1H), 7.24-7.20 (m, 2H), 6.68 (br m, 1H), 6.29 (d J=12.7, 1H), 6.18(d, J=12.7, 1H), 3.78-3.69 (m, 1H), 3.47-3.38 (m, 1H), 3.11-3.00 (m,1H), 1.33 (d, J=7.0, 3H).

F. (S)—N-2-Phenylpropyl maleimide. A mixture of(S)-E-3-(2-phenyl-propylcarbamoyl)-acrylic acid (1.44 g, 6.2 mmol),NaOAc (305 mg, 3.7 mmol), and Ac₂O (6 mL) was heated at 120° C. for 5 h.The mixture was concentrated, and the residue was stirred vigorouslywith satd. aq. NaHCO₃. The resulting mixture was extracted with DCM(3×). The combined organic layers were dried (Na₂SO₄) and concentrated.The crude product was purified by flash chromatography (EtOAc/hexanes)to provide 340 mg (26%) of the desired maleimide as a white solid. ¹HNMR (400 MHz, CDCl₃): 7.32-7.26 (m, 2H), 7.24-7.17 (m, 3H), 6.60 (s,2H), 3.70 (dd, J=13.7, 8.2, 1H), 3.61 (dd, J=13.7, 7.8, 1H), 3.23 (app.sextet, J=7.7, 1H), 1.26 (d, J=7.0, 3H).

G.(S)-[6-Bromo-1.3-dioxo-2-(2-phenyl-propyl)-2,3-dihydro-1H-isoindol-4-yl]-carbamicacid tert-butyl ester. A solution of 4-bromo-furan-2-carbonyl azide (444mg, 2.06 mmol) and (S)—N-2-phenylpropyl maleimide (340 mg, 1.58 mmol) indegassed tert-butanol (3 mL) was heated under N₂ at 70° C. for 24 h. Theresulting dark red solution was concentrated, and the residue wasadsorbed onto SiO₂ and purified by flash chromatography (EtOAc/hexanes)to give a pale yellow foam (160 mg, 22%). ¹H NMR (400 MHz, CDCl₃): 8.72(d, J=1.3, 1H), 8.69 (br s, 1H), 7.51 (d, J=1.5, 1H), 7.33-7.18 (m, 5H),3.81 (dd, J=13.6, 7.8, 1H), 3.73 (dd, J=13.6, 8.1, 1H), 3.36-324 (m,1H), 1.54 (s, 9H), 1.26 (d, J=7.0, 3H).

H. (S)-4-Amino-6-bromo-2-(2-phenyl-propyl)-isoindole-1,3-dione.(S)-[6-Bromo-1,3-dioxo-2-(2-phenyl-propyl)-2,3-dihydro-1H-isoindol-4-yl]-carbamicacid tert-butyl ester (160 mg, 0.35 mmol) was stirred in a mixture ofDCM (2 mL) and TFA (1 mL) for 3 h at rt. The mixture was concentrated,and the residue was diluted with satd. aq. NaHCO₃ and extracted with DCM(3×). The combined organic layers were dried (Na₂SO₄) and concentratedto give a yellow oil. Purification by flash chromatography(EtOAc/hexanes) gave 110 mg (87%) of the desired amine as a yellow foam.¹H NMR (500 MHz, CDCl₃): 7.31-7.23 (m, 4H), 7.22-7.17 (m, 2H), 6.81 (d,J=1.5, 1H), 5.19 (br s, 2H), 3.78 (dd, J=13.6, 7.6, 1H), 3.71 (dd,J=13.6, 8.2, 1H), 3.30 (app sextet, J_(app)=7.5, 1H), 1.29 (d, J=7.0,3H).

I. (S)-Benzo[1,2,5]thiadiazole-4-sulfonic acid[6-bromo-1,3-dioxo-2-(2-phenyl-propyl)-2,3-dihydro-1H-isoindol-4-yl]-amide.A mixture of (S)-4-amino-6-bromo-2-(2-phenyl-propyl)-isoindole-1,3-dione(30 mg, 0.08 mmol) and benzo[1,2,5]thiadiazole-4-sulfonyl chloride (150mg, 0.64 mmol) was heated to 170° C. forming a melt and stirred for 2 h.The mxiture was allowed to cool, and the solidified residue wasdissolved in EtOAc, and the solution was washed with satd. aq. NaHCO₃,dried (Na₂SO₄), and concentrated. Purification by flash chromatography(EtOAc/hexanes) gave the desired sulfonamide as a tan solid (30 mg,64%). HPLC: R_(T)=11.01 min. MS (ESI−): mass calcd. for C₂₃H₁₇BrN₄O₄S₂,555.99; m/z found, 555/557 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 9.59 (br s,1H), 8.39 (dd, J=7.0, 1.0, 1H), 8.27 (dd, J=8.8, 1.0, 1H), 8.08 (d,J=1.4, 1H), 7.75 (dd, J=8.8, 7.1, 1H), 7.47 (d, J=1.3, 1H), 7.27-7.22(m, 2H), 7.21-7.17 (m, 3H), 3.78 (dd, J=13.6, 8.1, 1H), 3.68 (dd,J=13.6, 7.81, 1H), 3.26 (sextet, J=7.4, 1H), 1.26 (d, J=7.0, 3H).

Example 14

(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionicacid

A. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acidmethyl ester. The title compound (0.95 g, 50%) was prepared from methyl2-amino-4,5-dichlorobenzoate and 4-chlorosulfonyl-2,1,3-benzothiadiazoleas in Example 1, Part A (without DMAP). ¹H NMR (500 MHz, CDCl₃): 11.21(s, 1H), 8.39 (dd, J=7.1, 1.0, 1H), 8.25 (dd, J=8.8, 1.0, 1H), 7.94 (s,1H), 7.91 (s, 1H), 7.74 (dd, J=8.8, 7.1, 1H), 3.93 (s, 3H).

B. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoicacid. To a solution of2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acidmethyl ester (0.95 g, 2.3 mmol) in THF (21 mL) and water (7 mL) wasadded LiOH.H₂O (0.38 g, 9.1 mmol). The biphasic mixture was stirredovernight at rt. The mixture was acidified with conc. HCl and extractedwith DCM (3×). The combined organic layers were dried (MgSO₄) andconcentrated to provide 0.80 g (88%) of the pure acid as a white solid.¹H NMR (500 MHz, CDCl₃): 11.07 (s, 1H), 8.41 (dd, J=7.0, 1.0, 1H), 8.27(dd, J=8.8, 1.0, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.75 (dd, J=8.8, 7.0,1H).

C.(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionicacid. (R)-2-(tert-Butoxycarbonylamino)-3-(4-chloro-phenyl)-propionicacid was treated as in EXAMPLE 2, Part A, to produce(R)-2-amino-3-(4-chloro-phenyl)-propionic acid methyl esterhydrochloride as a white solid. This salt was then coupled with2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid asin EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as inEXAMPLE 2, Part E, to afford the title compound. HPLC: R_(T)=10.35 min.MS (ESI−): mass calcd. for C₂₂H₁₅Cl₃N₄O₅S₂, 583.95; m/z found, 583/585[M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.07 (s, 1H), 8.34 (d, J=7.1, 1H),8.23 (d, J=8.8, 1H), 7.84 (s, 1H), 7.74-7.70 (m, 1H), 7.30-7.26 (m, 2H),7.24 (s, 1H), 7.07 (d, J=8.3, 2H), 6.38 (d, J=7.4, 1H), 5.00-4.97 (m,1H), 3.30 (dd, J=14.1, 5.9, 1H), 3.21 (dd, J=14.1, 5.9, 1H).

Example 15

(R)-3-(4-Chloro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid

A. 4-lodo-2-nitro-benzoic acid. In a 1 L three-neck round-bottom flaskequipped with an internal thermometer, a reflux condenser, and anaddition funnel, Bu₄N⁺MnO₄ ⁻ (124 g, 343 mmol) was dissolved in pyridine(200 mL). The solution was heated to 60° C., and then the heating sourcewas removed. A solution of 4-iodo-2-nitrotoluene (43.0 g, 163 mmol) inpyridine (60 mL) was added through the additional funnel over2 h. Thereaction temperature was maintained at 60° C. by adjusting the additionrate. When the addition was complete, the reaction mixture was cooled tort. The solution was concentrated, diluted with EtOAc (300 mL) and water(200 mL), and stirred at rt for 30 min. The precipitated brown solid wasfiltered off and washed with EtOAc. The clear organic layer was washedwith 5% aq. H₂SO₄ (200 mL) and brine (200 mL), dried (MgSO₄), andconcentrated to afford a thick, brown oil. The crude product wasdissolved in EtOAc (200 mL) and then a solution of KOH (9.1 g, 163 mmol)in MeOH (ca. 30 mL) was added dropwise. The mixture was stirred at rtfor 1 h, and the precipitated solid was collected by filtration andwashed with EtOAc. The filtrate was concentrated and the precipitationwas repeated with KOH in MeOH. The two crops were combined and dissolvedin water (ca. 250 mL) and acidified with conc. HCl to pH<2. Theprecipitated white solid was collected by filtration and dried undervacuum to give the desired product (40 g, 136 mmol, 83%, >98% purity byHPLC). ¹H NMR (400 MHz, CD₃OD): 8.13 (d, J=1.6, 1H), 8.01 (dd, J=8.1,1.6, 1H), 7.50 (d, J=8.1, 1H).

B. 2-Amino-4-iodo-benzoic acid. 4-lodo-2-nitro-benzoic acid (20 g, 68mmol, 1.0 equiv.) was dissolved in 200 mL of EtOAc and then SnCl₂.2H₂O(46 g, 204 mmol, 3.0 equiv.) was added in three portions. The reactionmixture was stirred at rt for 16 h. Satd. aq. NaHCO₃ was carefully addedto adjust the mixture to pH=9. The precipitated solid was removed byfiltration through diatomaceous earth, washing with water. The aqueouslayer in the filtrate was separated and acidified with conc. HCl topH=2. The precipitated solid was collected by filtration and dried toafford the title compound as white solid (19 g, 68 mmol, 100%). ¹H NMR(400 MHz, CD₃OD): ¹H NMR (500 MHz, CDCl₃): 7.56 (d, J=8.5, 1H), 7.08 (s,1H), 6.99 (d, J=8.5, 1H), 5.71 (br s, 2H).

C. 4-lodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid. A mixture of2-amino-4-iodo-benzoic acid (10 g, 38 mmol, 1.0 equiv.) andquinoxaline-5-sulfonyl chloride (8.7 g, 38 mmol) in 100 mL of water wasbasified with satd. aq. Na₂CO₃, with stirring, to adjust the pH to 8.0.As the reaction progressed, the pH was maintained at 8.0±0.2 by addingsatd. aq. Na₂CO₃. After 3 h, no further pH changes were observed. Thereaction mixture was stirred at rt for another 16 h. Conc. HCl was addedto adjust the pH to <2. The precipitated solid was collected byfiltration, washed with water and dried to afford the title compound aswhite solid (17 g, 37.4 mmol, 98%). MS(ESI+): calcd. for C₁₅H₁₀IN₃O₄S,455.0; m/z found, 456 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 14.0 (br s,1H), 11.6 (s, 1H), 9.10 (d, J=1.5, 1H), 9.97 (d, J=1.5, 1H), 8.60 (d,J=7.4, 1H), 8.42 (d, J=8.4, 1H), 8.06 (t, J=7.5, 1H), 7.95 (d, J=1.2,1,H), 7.51 (d, J=8.3, 1H), 7.37 (dd, J=8.3, 1.2, 1H).

D.(R)-3-(4-Chloro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid. (R)-2-(tert-Butoxycarbonylamino)-3-(4-chloro-phenyl)-propionicacid was treated as in EXAMPLE 2, Part A, to produce(R)-2-amino-3-(4-chloro-phenyl)-propionic acid methyl esterhydrochloride as a white solid. This ester was coupled with4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1,Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, PartE. HPLC: R_(T)=9.74 min. MS (ESI−): mass calcd. for C₂₄H₁₈ClIN₄O₅S,635.97; m/z found, 635/637 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 10.93 (d,J=12.8, 1H), 8.99 (d, J=1.6, 1H), 8.92 (s, 1H), 8.54 (d, J=7.4, 1H),8.31 (d, J=8.5, 1H), 8.10 (s, 1H), 7.90-7.87 (m, 1H), 7.30-7.22 (m, 3H),7.05 (d, J=8.4, 2H), 6.84 (d, J=8.2, 1H), 6.29 (d, J=7.9, 1H), 4.93-4.80(m, 1H), 3.24 (dd, J=14.3, 5.8, 1H), 3.16 (dd, J=14.2, 5.9, 1H).

Example 16

(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide

A. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoic acidmethyl ester. The title compound (1.56 g, 75%) was prepared frombenzo[1,2,5]thiadiazole-4-sulfonyl chloride and 2-amino-5-chloro-benzoicacid methyl ester as in Example 1, Part A. HPLC: R_(T)=10.77 min. MS(ESI+): mass calcd. for C₁₄H₁₀ClN₃O₄S₂, 382.98; m/z found, 406 [M+Na]⁺.¹H NMR (500 MHz, CDCl₃): 11.16 (s, 1H), 8.35 (dd, J=7.0, 1.0, 1H), 8.22(dd, J=8.8, 1.0, 1H), 7.82 (d, J=2.5, 1H), 7.72-7.68 (m, 2H), 7.34 (dd,J=9.0, 2.5, 1H), 3.92. (s, 3H).

B. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoic acid.LiOH.H₂O (0.68 g, 16.2 mmol) was added to a stirred solution of2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoic acid methylester (1.56 g, 4.06 mmol) in THF (15 mL) and water (5 mL). After 18 h,the solution was acidified to p˜2 with conc. HCl, diluted with water,and extracted with DCM (3×). The combined organic layers were dried(MgSO₄), and concentrated to provide the title compound (1.50 g, 100%).HPLC: R_(T)=9.48 min. MS (ESI−): mass calcd. for C₁₃H₈ClN₃O₄S₂, 368.96;m/z found, 368/370 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.07 (s, 1H), 8.38(dd, J=7.0, 1.0, 1H), 8.24 (dd, J=8.8, 1.0, 1H), 7.92 (d, J=2.5, 1H),7.75 (d, J=9.0, 1H), 7.71-7.69 (m, 1H), 7.40 (dd, J=9.0, 2.6, 1H).

C.(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide.The title compound was prepared from2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoic acid and(±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in. EXAMPLE 1,Part C. HPLC: R_(T)=11.76 min. MS (ESI−): mass calcd. forC₂₂H₁₇Cl₃N₄O₃S₂, 553.98; m/z found, 553/555 [M−H]⁻. ¹H NMR (400 MHz,CDCl₃): 11.05 (s, 1H), 8.30 (dd, J=7.0, 1.0, 1H), 8.21 (d, 8.0, 1H)7.70-7.66 (m, 1H), 7.65-7.63 (m, 1H), 7.41 (d, J=8.2, 1H), 7.29 (dd,J=4.6, 2.1, 2H), 7.05 (dd, J=9.6, 2.1, 2H), 5.80 (s, 1H), 3.67-3.60 (m,1H), 3.32-3.26 (m, 1H), 3.02-2.97 (m, 1H), 1.30 (d, J=7.0, 3H).

Example 17

(R)-2-[2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-3-phenyl-propionicacid

A. 2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-benzoic acid.2-Amino-4-iodo-benzoic acid was sulfonylated with2,6-difluorobenzenesulfonyl chloride as in EXAMPLE 1, Part A. ¹H NMR(500 MHz, CD₃OD): 8.05 (d, J=1.6, 1H), 7.72 (d, J=8.4, 1H), 7.68-7.60(m, 1H), 7.48 (dd, J=8.4, 1.6, 1H), 7.16-7.09 (m, 2H).

B.(R)-2-[2-(2.6-Difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-3-phenyl-propionicacid. (R)-2-(tert-Butoxycarbonylamino)-3-phenyl-propionic acid wastreated as in EXAMPLE 2, Part A, to produce(R)-2-amino-3-phenyl-propionic acid methyl ester hydrochloride as awhite solid. This ester was coupled with2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoic acid as in EXAMPLE1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2,Part E, to afford the title compound. HPLC: R_(T)=9.27 min. MS (ESI−):mass calcd. for C₂₂H₁₇F₂IN₂O₅S, 585.99; m/z found, 584/586[M−H]⁻. ¹H NMR(500 MHz, CDCl₃): 11.32 (s, 1H), 8.11 (s, 1H), 7.50-7.46 (m, 1H),7.38-7.28 (m, 4H), 7.16-7.15 (m, 2H), 7.00-6.96 (m, 3H), 6.51 (d, J=7.6,1H), 5.07-5.03 (m, 1H), 3.34 (dd, J=14.0, 5.6, 1H), 3.25 (dd, J=14.3,5.3, 1H).

Example 18

(±)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(3,4-dichloro-phenyl)-3-oxo-propionicacid methyl ester

A. 5-(3,4-Dichloro-phenyl)-oxazole-4-carboxylic acid methyl ester. Asolution of methyl isocyanoacetate (5.0 g, 50.0 mmol),3,4-dichlorobenzoyl chloride (10.6 g, 50.0 mmol), and Et₃N (20.9 mL, 150mmol) was stirred in THF (20 mL) for 48 h at rt. The solution wasconcentrated, diluted with EtOAc, washed with water, dried (MgSO₄), andconcentrated to afford a solid. The solid was washed with hexanes andcollected by filtration to provide 8.7 g (64%) of the desired product.HPLC: R_(T)=9.68 min. MS (ESI+): mass calcd. for C₁₁H₇Cl₂NO₃, 270.98;m/z found, 272/274 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.29 (d, J=2.1, 1H),8.03 (dd, J=8.5, 2.1, 1H), 7.94 (s, 1H), 7.56 (d, J=8.5, 1H), 3.98 (s,3H).

B. (±)-2-Amino-3-(3,4-dichloro-phenyl)-3-oxo-propionic acid methyl esterhydrochloride. A suspension of5-(3,4-dichloro-phenyl)-oxazole-4-carboxylic acid methyl ester (1.5 g,5.51 mmol), 3 N HCl (10 mL), and MeOH (15 mL) was heated at 50° C. for 4h. The mixture was concentrated, diluted with water, and washed withEt₂O. The aqueous layer was concentrated and Et₂O was added, causingprecipitation of a white solid. The precipitate was collected byfiltration to provide 1.0 g (63%) of the desired product as an apparent10:1 mixture of keto-enol tautomers. MS (ESI+): mass calcd. forC₁₀H₉Cl₂NO₃, 261.00; m/z found, 262/264[M+H]⁺. Major tautomer: ¹H NMR(500 MHz, CDCl₃): 8.32 (d, J=2.1, 1H), 8.094 (dd, J=8.4, 2.1, 1H), 7.79(d, J=8.5, 1H), 3.80 (s, 3H). Minor tautomer: ¹H NMR (500 MHz, CDCl₃):8.19 (d, J=2.0, 1H), 7.96 (dd, J=8.4, 2.1, 1H), 7.76id, J=8.4, 1H),6.18(s, 1H).

C.(±)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(3,4-dichloro-phenyl)-3-oxo-propionicacid methyl ester. 4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acidwas coupled to (±)-2-amino-3-(3,4-dichloro-phenyl)-3-oxo-propionic acidmethyl ester hydrochloride as in EXAMPLE 1, Part C. HPLC: R_(T)=10.65min. MS (ESI+): mass calcd. for C₂₅H₁₇Cl₃N₄O₆S, 605.99; m/z found,607/609 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 11.23 (s, 1H), 8.88 (d, J=1.8,1H), 8.85 (d, J=1.8, 1H), 8.58 (dd, J=7.4, 1.4, 1H), 8.32 (dd, J=8.5,1.4, 1H), 8.24 (d, 2.1, 1H), 8.03 (dd, J=8.4, 2.1, 1H), 7.89-7.86 (m,1H), 7.79 (d, J=2.0, 1H), 7.69 (d, J=8.4, 1H), 7.45 (d, J=8.5, 1H), 7.30(d, J=6.9, 1H), 6.97 (dd, J=8.4, 2.0, 1H), 6.19 (d, J=6.9, 1H), 3.78 (s,3H).

Example 19

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionicacid

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-oxo-propionicacid methyl ester was prepared as in EXAMPLE 18, substituting2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid inPart C. A suspension of the methyl ester (34 mg, 0.055 mmol) in EtOH(0.6 mL) was treated with NH₄Cl (59 mg, 1.11 mmol), water (0.2 mL), andNaBH₄ (10 mg, 0.277 mmol). The resulting yellow, homogenous suspensionwas stirred at rt for 1 h. The mixture was diluted with water andextracted with DCM (3×). The combined organic layers were dried (MgSO₄)and concentrated to provide the crude product. The crude product wasdissolved in DMF (˜1 mL) and purified by preparative reversed-phase HPLCto provide the desired product as a white solid as a 9:1 mixture ofdiastereomers (11 mg, 33%). HPLC: R_(T)=10.16 min (major diastereomer)and 10.26 min (minor diastereomer). MS (ESI−): mass calcd. forC₂₂H₁₅Cl₃N₄O₆S₂, 601.9; m/z found, 601 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃):Major diastereomer: 11.41 (s, 1H), 8.33 (d, J=6.9, 1H), 8.18 (d, J=8.8,1H), 7.73-7.68 (m, 1H), 7.58 (br s, 1H), 7.44 (br s, 1H), 7.38-7.34 (m,1H), 7.23-7.16 (m, 2H), 7.03 (br d, J=6.6, 1H), 6.83 (br d, J=7.9, 1H),5.83 (br d, J=3.9, 1H), 5.16-5.09 (br m, 1H); Minor diastereomer: 11.01(s, 1H), 8.29 (d, J=6.9, 1H), 8.14 (d, J=9.4, 1H), 7.70-7.63 (m, 1H),7.53-7.49 (br m, 2H), 7.34-7.30 (m, 1H), 7.18-7.10 (m, 2H), 7.02-7.00(m, 1H), 6.82-6.78 (m, 1H), 5.61-5.56 (br m, 1H), 5.06-5.02 (br m, 1H).

Example 20

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-methyl-N-phenethyl-benzamide

A. 4-Bromo-2-nitrobenzoic acid. A mixture of 4-bromo-2-nitrotoluene (5.0g, 23 mmol), KMnO₄ (10.9 g, 69 mmol), and water (250 mL) was heated atreflux overnight. The mixture was filtered through a pad of diatomaceousearth, washing with water. The basic filtrate was acidified to pH˜1 withconc. HCl and extracted with EtOAc (3×300 mL). The combined organiclayers were dried (MgSO₄) and concentrated to provide the desiredbenzoic acid (1.22 g, 22%). MS (ESI−): mass calcd. for C₇H₄BrNO₄, 244.9;m/z found, 244 [M−H]⁻. ¹H NMR (400 MHz, CD₃OD): 8.07 (d, J=1.9, 1H),7.85 (dd, J=8.2, 1.9, 1H), 7.65 (d, J=8.2, 1H).

B. Methyl 2-amino-4-bromobenzoate. To a stirred solution of4-bromo-2-nitrobenzoic acid (3.81 g, 15 mmol) in DMF (30 mL) at 0° C.was added 1,8-diazabicycloundecane (DBU; 10.3 mL, 75 mmol) followed byMel (4.67 mL, 75 mmol). The mixture was stirred for 15 min at 0° C.,then was allowed to warm to rt and was stirred overnight. The mixturewas poured into water and extracted with EtOAc (2×). The combinedorganic extracts were washed with water (2×), dried (MgSO₄), andconcentrated. The residue was purified by flash chromatography(hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a paleyellow solid (3.52 g, 90%). To a solution of the nitrobenzoate (3.52 g,13.5 mmol) in 1:1 EtOAc/DCM (30 mL) at rt was added SnCl₂.2H₂O (15.27 g,67 mmol). After 18 h, the mixture was concentrated, diluted with satd.aq. NaHCO₃, and extracted with DCM (3×). The combined organic layerswere dried (MgSO₄) and concentrated to provide the desired aminobenzoateas a white solid (2.89 g, 93%). 1H NMR (400 MHz, CDCl₃): 7.70(d, J=8.6,1H), 6.84 (d, J=1.9, 1H), 6.75 (dd, J=8.6, 1.9, 1H), 5.78 (br s, 2H),3.86 (s, 3H).

C. 2-Benzo1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoic acid methylester. The title compound (3.95 g, 75%) was prepared from methyl2-amrino-4-bromobenzoate and 4-chlorosulfonyl-2,1,3-benzothiadiazole asin Example 1, Part A. MS (ESI−): mass calcd. for C₁₄H₁₀BrN₃O₄S₂, 426.9;m/z found, 426 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.34 (br s, 1H), 8.40(dd, J=7.0, 0.9, 1H), 8.24 (dd, J=8.8, 0.9, 1H), 7.92 (d, J=1.8, 1H),7.74 (dd, J=8.8, 7.0, 1H), 7.72 (d, J=8.5, 1H), 7.10 (dd, J=8.5, 1.8,1H), 3.92 (s, 3H).

D. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromobenzoic acid. Thetitle compound (2.79 g, 98%) was prepared as in Example 1, Part B. ¹HNMR (500 MHz, CDCl₃): 11.14 (br s, 1H), 8.42 (dd, J=7.2, 1.1, 1H), 8.26(dd, J=8.8, 1.1, 1H), 7.98 (d, J=1.6, 1H), 7.82 (d, J=8.5, 1H), 7.75(dd, J=8.8, 7.2, 1H), 7.16 (dd, J=8.5, 1.6, 1H).

E.2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-methyl-N-phenethyl-benzamide.2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromobenzoic acid wascoupled with N-methylphenethylamine as in EXAMPLE 1, Part C. HPLC:R_(T)=9.90 min. MS (ESI−): mass calcd. for C₂₂H₁₉BrN₄O₃S₂, 530.01; m/zfound, 529/531 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃; rotameric broadening):8.95-8.80 (br s, 0.6H), 8.57-8.43 (br s, 0.4H), 8.27 (dd, J=7.0, 0.9,1H), 8.23 (br d, J=8.8, 1H), 7.80-7.64 (m, 2H), 7.37-6.85 (br m, 6H),6.73-6.62 (br m, 0.6H), 6.55-6.40 (br m, 0.4H), 3.68-3.35 (br m, 1.3H),3.35-3.07 (br m, 0.7H), 3.07-2.25 (br m, 5H).

Example 21

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-[2-(4-chloro-phenyl)-propyl]-benzamide

This compound was prepared as in EXAMPLE 5, Parts C and D, substituting4-chloro-β-methyl phenethylamine hydrochloride in Part C. HPLC:R_(T)=10.82 min. MS (ESI−): mass calcd. for C₂₂H₁₈BrClN₄O₃S₂, 565.9; m/zfound, 565 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.49 (s, 1H), 8.34 (dd,J=7.0, 0.6, 1H), 8.22 (dd, J=8.8, 0.7, 1H), 7.86 (d, J=1.7, 1H), 7.72(dd, J=8.8, 7.0, 1H), 7.31-7.29 (m, 2H), 7.14-7.11 (m, 2H), 7.03 (dd,J=8.4, 1.8, 1H), 6.88 (d, J=8.4, 1H), 5.82-5.79 (br m, 1H), 3.72 (td,J=13.1, 6.4, 1H), 3.30 (ddd, J=13.7, 8.9, 5.2, 1H), 3.03-2.98 (m, 1H),1.30(d, J=7.0, 3H).

Example 22

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-1-methyl-ethyl]-4-trifluoromethyl-benzamide

This compound was prepared as in EXAMPLE 3, Parts A and B, and EXAMPLE5, Part D. HPLC (reversed-phase): R_(T)=11.00 min. MS (ESI−): masscalcd. for C₂₃H₁₈ClF₃N₄O₃S₂, 555.0; m/z found, 554 [M−H]⁻. ¹H NMR (400MHz, CDCl₃): 11.25 (s, 1H), 8.37 (dd, J=7.0, 0.8, 1H), 8.23 (dd, J=8.8,0.9, 1H), 7.94 (s, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.30-7.28 (m, 3H),7.20 (d, J=8.2, 1H), 7.13 (d, J=8.3, 2H), 5.95 (d, J=7.9, 1H), 4.40-4.35(m, 1H), 2.84 (ddd, J=20.7, 13.6, 6.5, 2H), 1.21 (d, J=6.7, 3H).

Example 23

2-(Benzothiazole-4-sulfonylamino)-4-bromo-N-[2-(4-chloro-phenyl)-1-methyl-ethyl]-benzamide

This compound was prepared as in EXAMPLE 5, Parts C and D, substituting4-chloro-β-methyl phenethylamine hydrochloride in Part C. HPLC:R_(T)=10.62 min. MS (ESI−): mass calcd. for C₂₃H₁₉BrClN₃O₃S₂, 564.9; m/zfound, 564 [M−H]⁻. ¹H NMR (400 mHz CDCl₃): 11.19 (s, 1H), 9.16 (s, 1H),8.93 (d, J=4.1, 1H), 8.20 (dd, J=17.0, 7.3, 2H), 7.91-7.89 (m, 1H), 7.81(s, 1H), 7.60-7.56 (m, 1H), 7.11 (d, J=7.6, 2H), 7.04 (s, 1H), 5.79-5.82(m, 1H), 4.37-4.34 (m, 1H), 2.78-2.73 (m, 1H), 2.89-2.86 (m, 1H), 1.17(d, J=6.1, 3H).

Example 24

4-Bromo-N-[2-(4-chloro-phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-benzamide

This compound was prepared as in EXAMPLE 5, Parts C and D, substituting4-chloro-β-methyl phenethylamine hydrochloride in Part C. HPLC:R_(T)=10.85 min. MS (ESI−): mass calcd. for C₂₂H₁₈BrClF₂N₂O₃S, 543.8;m/z found, 543 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.59 (s, 1H), 7.85 (d,J=1.7, 1H), 7.52-7.44 (m, 1H), 7.32-7.28 (m, 2H), 7.19-7.14 (m, 2H),7.13-7.10 (m, 1H), 7.05-6.96 (m, 3H), 6.14-6.12 (m, 1H), 3.73 (td,J=13.1, 6.4, 1H), 3.38 (ddd, J=13.8, 8.8, 5.3, 1H), 3.07 (m, 1H), 1.31(d, J=6.98, 3H).

Example 25

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-phenyl-propionicacid

This compound was prepared as in EXAMPLE 2, Parts B-E, substituting4-bromo-2-nitrobenzoic acid and (L)-phenylalanine methyl esterhydrochloride in Part B. HPLC: R_(T)=9.55 min. MS (ESI−): mass calcd.for C₂₂H₁₇BrN₄O₅S₂, 561.4; m/z found, 560 [M−H]³¹ . ¹H NMR (400 MHz,CDCl₃): 11.35 (s, 1H), 8.35 (dd, J=7.1, 0.9, 1H), 8.20 (dd, J=8.8, 0.9,1H), 7.89 (d, J=1.7, 1H), 7.71 (dd, J=8.8, 7.1, 1H), 7.31-7.26 (m, 3H),7.14-7.11 (m, 2H), 7.06-7.04 (m, 1H), 7.03-6.98 (m, 1H), 6.34 (d, J=7.3,1H), 5.01 (dd, J=13.1, 5.8, 1H), 3.32 (dd, J=14.1, 5.8, 1H), 3.24(dd,J=14.1, 5.8, 1H).

Example 26

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-trifluoromethyl-benzoylamino]-3-phenyl-propionicacid

This compound was prepared as in EXAMPLE 3, Parts C-F, substituting2-amino-4-trifluoromethyl-benzoic acid in Part B. HPLC: R_(T)=9.70 min.MS (ESI−): mass calcd. for C₂₃H₁₇F₃N₄O₅S₂, 550.5; m/z found, 550 [M−H]⁻.¹H NMR (400 MHz, CDCl₃): 11.21 (s, 1H), 8.36 (dd, J=7.1, 1.0), 8.19 (dd,J=8.8, 0.9, 1H), 7.99 (s, 1H), 7.70 (dd, J=8.8, 7.1, 1H), 7.29 (m, 4H),7.15 (dt, J=7.3, 1.3, 3H), 6.44 (d, J=7.4, 1H), 5.04 (dd, J=13.2, 5.8,1H), 3.35 (dd, J=14.2, 5.7, 1H), 3.26 (dd, J=14.1, 5.9, 1H).

Example 27

2-[4-lodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-phenyl-propionicacid

This compound was prepared as in EXAMPLE 2, Parts B-E, substituting(L)-phenylalanine methyl ester hydrochloride in Part B. HPLC: R_(T)=9.33min. MS (ESI−): mass calcd. for C₂₄H₁₉IN₄O₅S, 602,4; m/z found, 601[M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.00 (s, 1H), 8.99 (d, J=1.7, 1H),8.89 (d, J=1.7, 1H), 8.54 (dd, J=7.4, 1.3, 1H), 8.30 (dd, J=8.5, 1.3,1H), 8.13 (d, J=1.5, 1H), 7.87 (dd, J=8.4, 7.5, 1H), 7.29 (m, 2H), 7.11(dd, J=7.3, 2.0, 1H), 6.80 (d, J=8.3, 1,H), 6.24 (d, J=7.4, 1H), 4.92(dd, J=13.4, 5.9, 1H), 3.26 (dd, J=14.1, 5.8, 1H), 3.194,dd, J=14.1,6.0, 1H).

Example 28

2-[2-(Benzothiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-phenyl-propionicacid

This compound was prepared as in EXAMPLE 2, Parts B-E, substituting(L)-phenylalanine methyl ester hydrochloride in Part B,benzothiazole-4-sulfonyl chloride in Part D. HPLC: R_(T)=9.42 min. MS(ESI−): mass calcd. for C₂₃H₁₈IN₃O₅S₂, 607.4; m/z found, 606 [M−H]⁻. ¹HNMR (400 MHz, CDCl₃): 11.01 (s, 1H), 9.20 (s, 1H), 8.23 (d, J=7.6, 1H),8.17 (d, J=8.0, 1H), 8.01 (d, J=1.2, 1H), 7.58 (t, J=7.9, 1H), 7.25 (m,2H), 7.15 (m, 2H), 6.85 (d, J=8.2, 1H), 6.47 (d, J=6.8, 1H), 5.04 (dd,J=12.7, 6.0, 1H), 3.33 (dd, J=14.2, 5.5, 1H), 3.25 (dd, J=14.0, 6.0,1H).

Example 29

2-[4,5-Dichloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-phenyl-propionicacid

This compound was prepared as in EXAMPLE 3, substitutingquinoxaline-5-sulfonyl chloride in Part F. HPLC: R_(T)=9.46 min. MS(ESI−): mass calcd. for C₂₄H₁₈Cl₂N₄O₅S, 545.4; m/z found, 544 [M−H]⁻. ¹HNMR (400 MHz, CDCl₃): 10.90 (s, 1H), 8.99 (d, J=1.2, 1H), 8.90 (d,J=1.0, 1H), 8.52 (dd, J=7.3, 0.9, 1H), 8.30 (dd, J=8.5, 0.8, 1H), 7.86(m, 2H), 7.28 (m, 1H), 7.21 (m, 1H), 7.12 (dd, J=7.6, 1.8, 2H), 6.36 (d,J=7.4, 1H), 4.90 (dd, J=13.5, 6.1, 1H), 3.25 (dd, J=14.0, 5.6, 1H), 3.17(dd, J=14.0, 6.3, 1H).

Example 30

4-Bromo-N-[2-(3,4-dichloro-phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-benzamide

This compound was prepared as in EXAMPLE 5, substituting2,6-difluoro-benzenesulfonyl chloride in Part D. HPLC: R_(T)=11.05 min.MS (ESI−): mass calcd. for C₂₂H₁₇BrCl₂F₂N₂O₃S, 578.3; m/z found, 577[M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.58 (s, 1H), 7.88 (d, J=1.8, 1H),7.54-7.46 (m, 1H), 7.41 (d, J=8.3, 1H), 7.32 (d, J=2.1, 1H), 7.15-7.12(m, 1H), 7.10-7.05 (m, 1H), 7.02-6.96 (m, 2H), 6.07 (br m, 1H), 3.73(td, J=13.1, 6.4, 1H), 3.38 (ddd, J=13.8, 8.7, 5.5, 1H), 3.12-3.01 (m,1H), 1.32 (d, J=7.0, 3H).

Example 31

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-(2-phenyl-propyl)-benzamide

This compound was prepared as in EXAMPLE 5, Parts C and D, substituting(−)-β-methylphenethylamine hydrochloride in Part C. HPLC: R_(T)=10.17min. MS (ESI−): mass calcd. for C₂₂H₁₉BrN₄O₃S₂, 531.5; m/z found, 530[M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.51 (s, 1H), 8.32 (dd, J=7.0, 0.8,1H), 8.20(dd, J=8.8, 0.8, 1H), 7.83 (d, J=1.8, 1H), 7.70 (dd, J=8.8,7.1, 1H), 7.34-7.31 (m, 2H), 7.26-7.18 (m, 3H), 7.00 (dd, J=8.4, 1.8,1H), 6.85 (d, J=8.4, 1H), 5.90 (br m, 1H), 3.77-3.70 (m, 1H), 3.30 (ddd,J=13.6, 9.0, 4.9, 1H), 3.04-2.96 (m, 1H), 1.32 (d, J=7.0, 3H).

Example 32

3-(3,4-Dichloro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-propionicacid

This compound was prepared as in EXAMPLE 2,substituting-2,6-difluoro-benzenesulfonyl chloride in Part D. HPLC:R_(T)=9.94 min. MS (ESI−): mass calcd. for C₂₂H₁₅Cl₂F₂IN₂O₅S, 655.2; m/zfound, 654 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.29 (s, 1H), 8.05 (d,J=1.4, 1H), 7.53-7.45 (m, 1H), 7.39-7.36 (m, 2H), 7.27-7.26 (m, 1H),7.07-6.96 (m, 3H), 6.77 (d, J=7.3, 1H), 5.00 (q, J=6.0, 1H), 3.32 (dd,J=14.2, 5.7, 1H), 3.19 (dd, J=14.2, 6.2, 1H).

Example 33

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-propionicacid

This compound was prepared as in EXAMPLE 2, substituting(S)-2-tert-butoxycarbonylamino-3-(4-chloro-phenyl)-propionic acid inPart A. HPLC: R_(T)=9.72 min. MS (ESI−): mass calcd. forC₂₂H₁₆ClIN₄O₅S₂, 642.9; m/z found, 642[M−H]⁻. ¹H NMR (400 MHz, CDCl₃):11.31 (s, 1H), 8.37 (dd, J=6.9, 0.6, 1H), 8.22 (d, J=8.8, 1H), 8.08 (d,J=1.4, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.33-7.19 (m, 3H), 7.05 (d,J=8.4, 2H), 6.88 (d, J=8.3, 1H), 6.40 (d, J=7.3, 1H), 4.99 (q, J=5.7,1H), 3.30 (dd, J=14.2, 5.6), 3.21 (dd, J=14.3, 5.4, 1H).

Example 34

3-(4-Chloro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-propionicacid

This compound was prepared as in EXAMPLE 2, substituting(S)-2-tert-butoxycarbonylamino-3-(4-chloro-phenyl)-propionic acid inPart A and 2,6-difluoro-benzenesulfonyl chloride in Part D. HPLC:R_(T)=9.71 min. MS (ESI−): mass calcd. for C₂₂H₁₆ClF₂IN₂O₅S, 620.8; m/zfound, 620 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.33 (s, 1H), 8.06 (d,J=1.4, 1H), 7.53-7.46 (m, 1H), 7.36 (dd, J=8.3, 1.4, 1H), 7.27-7.25 (m,2H), 7.10 (d, J=8.4, 2H), 7.05-6.96 (m, 2H), 6.72 (d, J=7.4, 1H), 6.32(br s, 1H), 4.99 (q, J=6.0, 1H), 3.31 (dd, J=14.2, 5.7, 1H), 3.19 (dd,J=14.2, 6.2, 1H).

Example 35

(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-(2-phenyl-propyl)-benzamide

This compound was prepared as in EXAMPLE 5, Parts C and D, substituting(R)-β-methyl phenethylamine in Part C. HPLC: R_(T)=11.06 min. MS (ESI−):mass calcd. for C₂₂H₁₉BrN₄O₃S₂, 531.5; m/z found, 530 [M−H]⁻. ¹H NMR(400 MHz, CDCl₃): 11.43 (s, 1H), 8.33 (dd, J=7.1, 0.9, 1H), 8.21 (dd,J=8.8, 0.9, 1H), 7.84 (d, J=1.8, 1H), 7.70 (dd, J=8.8, 7.1, 1H),7.35-7.31 (m, 2H), 7.26-7.23 (m, 1H), 7.20-7.18 (m, 2H), 7.00 (dd,J=8.4, 1.8, 1H), 6.84 (d, J=8.4, 1H), 5.85 (br m, 1H), 4.50 (br s, 1H),3.78-3.72 (m, 1H), 3.30 (ddd, J=13.7, 9.1, 4.9, 1H), 3.06-2.95 (m, 1H),1.33 (d, J=7.0, 3H).

Example 36

(R)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-(2-phenyl-propyl)-benzamide

This compound was prepared as in EXAMPLE 5, Parts C and D, substituting(S)-β-methyl phenethylamine in Part C. HPLC: R_(T)=11.05 min. MS (ESI−):mass calcd. for C₂₂H₁₉BrN₄O₃S₂, 531.5; m/z found, 530 [M−H]⁻. ¹H NMR(400 MHz, CDCl₃): 11.41 (s, 1H), 8.33 (dd, J=7.1, 0.9, 1H), 8.21 (dd,J=8.8, 0.9, 1H), 7.84 (d, J=1.8, 1H), 7.70 (dd, J=8.8, 7.1, 1H),7.35-7.31 (m, 2H), 7.26-7.23 (m, 1H), 7.20-7.18 (m, 2H), 7.01 (dd,J=8.4, 1.8, 1H), 6.83 (d, J=8.4, 1H), 5.86 (br m, 1H), 4.68 (br s, 1H),3.72-3.78 (m, 1H), 3.30 (ddd, J=13.6, 9.1, 4.9, 1H), 3.04-2.95 (m, 1H),1.33 (d, J=7.0, 3H).

Example 37

(S)-4-Bromo-2-(2,6-difluoro-benzenesulfonylamino)-N-(2-phenyl-propyl)-benzamide

This compound was prepared as in EXAMPLE 5, Parts C and D, substituting(R)-β-methyl phenethylamine in Part C, 2,6-difluoro-benzenesulfonylchloride in Part D. HPLC: R_(T)=11.11 min. MS (ESI−): mass calcd. forC₂₂H₁₉BrF2N₂O₃S, 509.4; m/z found, 508 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃):11.44 (s, 1H), 7.86 (d, J=1.8, 1H), 7.53-7.45 (m, 1H), 7.37-7.34 (m,2H), 7.29-7.22 (m, 3H), 7.10 (dd, J=8.4, 1.8, 1H), 7.01-6.95 (m, 3H),6.06-6.04 (br m, 1H), 5.50 (br s, 1H), 3.84-3.77 (m, 1H), 3.40-3.33 (m,1H), 3.13-3.02 (m, 1H), 1.34 (d, J=7.0, 3H).

Example 38

(R)-4-Bromo-2-(2,6-difluoro-benzenesulfonylamino)-N-(2-phenyl-propyl)-benzamide

This compound was prepared as in EXAMPLE 5, Parts C and D, substituting(S)-β-methyl phenethylamine in Part C, 2,6-difluoro-benzenesulfonylchloride in Part D. HPLC: R_(T)=11.11 min. MS (ESI−): mass calcd. forC₂₂H₁₉BrF₂N₂O₃S, 509.4; m/z found, 508 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃):11.49 (s, 1H), 7.86 (d, J=1.8, 1H), 7.45-7.52 (m, 1H), 7.40-7.33 (m,2H), 7.28-7.22 (m, 3H), 7.10 (dd, J=8.4, 1.8, 1H), 7.01-6.96 (m, 3H),6.05 (br m, 1H), 5.21 (br s, 1H), 3.84-3.77 (m, 1H), 3.37 (ddd, J=13.7,9.1, 5.0, 1H), 3.08-3.04 (m, 1H), 1.34 (d, J=7.0, 3H).

Example 39

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(3,4-dichloro-phenyl)-propyl]-4-iodo-benzamide

This compound was prepared as in EXAMPLE 5, substituting4-iodo-2-nitrobenzoic acid in Part C. HPLC: R_(T)=11.97 min. MS (ESI−):mass calcd. for C₂₂H₁₇Cl₂IN₄O₃S₂, 647.3; m/z found, 646 [M−H]⁻. ¹H NMR(400 MHz, CDCl₃): 11.40 (s, 1H), 8.34 (dd, J=7.0, 0.9, 1H), 8.23 (dd,J=8.8, 0.9, 1H), 8.04 (d, J=1.6, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.39(d, J=8.2, 1H), 7.29-7.25 (m, 2H), 7.04 (dd, J=8.3, 2.1, 1H), 6.77 (d,J=8.3, 1H), 5.92-5.90 (br m, 1H), 3.71-3.64 (m, 1H), 3.30 (ddd, J=13.7,8.6, 5.4, 1H), 3.04-2.98 (m, 1H), 1.30 (d, J=7.0, 3H).

Example 40

N-[2-(3,4-Dichloro-phenyl)-propyl]-4-iodo-2-(quinoxaline-5-sulfonylamino)-benzamide

This compound was prepared as in EXAMPLE 5, substitutingquinoxaline-5-sulfonyl chloride in Part D. HPLC: R_(T)=11.49 min. MS(ESI−): mass calcd. for C₂₄H₁₉Cl₂IN₄O₃S, 641.3; m/z found, 640 [M−H]⁻.¹H NMR (400 MHz, CDCl₃): 11.13 (s, 1H), 9.01 (d, J=1.7, 1H), 8.95 (d,J=1.7, 1H), 8.54 (dd, J=7.4, 1.3, 1H), 8.33 (dd, J=8.5, 1.3, 1H), 8.03(d, J=1.6, 1H), 7.89 (dd, J=8.4, 7.5, 1H), 7.38 (d, J=8.23, 1H), 7.28(d, J=2.0, 1H), 7.23 (dd, J=8.2, 1.6, 1H), 7.03 (dd, J=8.3, 2.1, 1H),6.77 (d, J=8.3, 1H), 5.96-5.94 (br m, 1H), 3.60-3.56 (m, 1H), 3.29 (ddd,J=13.7, 8.5, 5.5, 1H), 3.01-2.95 (m, 1H), 1.29 (d, J=7.0, 1H).

Example 41

2-[4-Bromo-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino]-3-(2,4-dichloro-phenyl)-propionicacid

A. 2-(2.6-Difluoro-benzenesulfonylamino)-4-bromo-benzoic acid. Methyl2-amino-4-bromobenzoate was sulfonylated with2,6-difluorobenzenesulfonyl chloride and hydrolyzed as in EXAMPLE 1,Part B. ¹H NMR (400 MHz, acetone-d₆): 11.65 (s, 1H), 8.02 (d, J=8.5,1H), 7.93 (d, J=1.8, 1H), 7.74-7.82 (m, 1H), 7.38 (dd, J=8.5. 1.9, 1H),7.28-7.23 (m, 2H).

B.2-[4-Bromo-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino]-3-(2,4-dichloro-phenyl)-propionicacid. (S)-2-Amino-3-(2,4-dichloro-phenyl)-propionic acid was treated asin EXAMPLE 2, Part A, to produce(S)-2-amino-3-(2,4-dichloro-phenyl)-propionic acid methyl esterhydrochloride as a white solid. This ester was coupled with4-bromo-2-(2,6-difluoro-benzenesulfonylamino)-benzoic acid as in EXAMPLE1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2,Part E, to afford title compound. HPLC: R_(T)=10.26 min. MS (ESI−): masscalcd. for C₂₂H₁₅BrCl₂F₂N₂O₅S, 608.2; m/z found, 607 [M−H]⁻. ¹H NMR (400MHz, CDCl₃): 11.36 (s, 1H), 7.87 (d, J=1.8, 1H), 7.52-7.44 (m, 1H), 7.39(d, J=1.6, 1H), 7.27-7.25 (m, 1H), 7.25-7.22 (m, 1H), 7.18-7.15 (m, 1H),6.97 (t, J=8.7, 2H), 6.79 (d, J=7.7, 1H), 5.05-5.00 (m, 1H), 3.50 (dd,J=14.2, 5.5, 1H), 3.29 (dd, J=14.2, 8.1, 1H).

Example 42

N-[2-(3,4-Dichloro-phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzamide

This compound was prepared from2-(2,6-difluorobenzenesulfonylamino)-4-iodo-benzoic acid and2-(3,4-dichloro-phenyl)-propylamine as in EXAMPLE 1, Part C. HPLC:R_(T)=11.98 min. MS (ESI−): mass calcd. for C₂₂H₁₇Cl₂F₂IN₂O₃S, 625.3;m/z found, 624 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.63 (s, 1H), 8.02 (d,J=1.5, 1H), 7.54-7.45 (m, 1H), 7.39 (d, J=8.2, 1H), 7.34 (d, J=1.6, 1H),7.32 (d, J=1.8, 1H), 7.09 (dd, J=8.3, 2.1, 1H), 7.02-6.94 (m, 3H),6.34-6.32 (br m, 1H), 3.743.65 (m, 1H), 3,40 (ddd, J=13.7, 8.5, 5.6,1H), 3.14-3.04 (m, 1H), 1.30 (d, J=7.0, 3H).

Example 43

4-Chloro-N-[2-(2,4-dichloro-phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-benzamide

A. 2-(2,6-Difluoro-benzenesulfonylamino)-4-chloro-benzoic acid. Methyl2-amino-4-chlorobenzoate was sulfonylated with2,6-difluorobenzenesulfonyl chloride and hydrolyzed as in EXAMPLE 1,Parts A and B.

B.4-Chloro-N-2-(2,4-dichloro-Phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-benzamide.The title compound was prepared from2-(2,6-difluoro-benzenesulfonylamino)-4-chloro-benzoic acid and2-(2,4-dichloro-phenyl)-propylamine hydrochloride (prepared as inEXAMPLE 5, substituting 2,4-dichlorophenyl-acetonitrile in Part A) as inExample 1, Part C. HPLC: R_(T)=11.20 min. MS (ESI−): mass calcd. forC₂₂H₁₇Cl₃F₂N₂O₃S, 533.8; m/z found, 533 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃):11.62 (s, 1H), 7.73 (d, J=1.9, 1H), 7.52-7.45 (m, 1H), 7.40 (d, J=1.8,1H), 7.28-7.25 (m, 2H), 7.18 (d, J=8.5, 1H), 7.01-6.96 (m, 3H), 6.05 (brm, 1H), 3.76-3.70 (m, 1H), 3.68-3.57 (m, 1H), 3.57-3.49 (m, 1H), 1.32(d, J=6.8, 3H).

Example 44

4-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-N-[2-(4-nitro-phenyl)-propyl]-benzamide

This compound was prepared from4-chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoic acid and2-(4-nitro-phenyl)-propylamine hydrochloride (prepared as in EXAMPLE 5,substituting 4-nitrophenylacetonitrile in Part A) as in Example 1, PartC. HPLC: R_(T)=10.37 min. MS (ESI−): mass calcd. for C₂₂H₁₈ClF₂N₃O₅S,509.9; m/z found, 509 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.63 (s, 1H),8.18 (d, J=8.6, 1H), 7.69 (d, J=1.7, 1H), 7.56-7.46 (m, 1H), 7.42 (d,J=8.6, 2H), 7.15 (d, J=8.5, 1H), 7.02-6.94 (m, 1H), 6.19-6.17 (br m,1H), 3.79-3.70 (m, 1H), 3.57-3.49 (m, 1H), 3.33-3.23 (m, 1H), 1.38 (d,J=6.9, 3H).

Example 45

4-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-N-[2-(4-trifluoromethyl-phenyl)-propyl]-benzamide

This compound was prepared from4-chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoic acid and2-(4-trifluoro-phenyl)-propylamine hydrochloride (prepared as in EXAMPLE5, substituting 4-trifluorophenyl-acetonitrile in Part A) as in Example1, Part C. HPLC: R_(T)=10.93 min. MS (ESI−): mass calcd. forC₂₃H₁₈ClF₅N₂O₃S, 532.9; m/z found, 532 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃):11.64 (s, 1H), 7.72 (d, J=2.0, 1H), 7.61 (d, J=8.1, 2H), 7.53-7.46 (m,1H), 7.36 (d, J=8.1, 2H), 7.10 (d, J=8.5, 1H), 7.01-6.94 (m, 3H), 6.02(br m, 1H), 3.83-3.74 (m, 1H), 3.45 (ddd, J=13.8, 8.7, 5.4, 1H),3.23-3.13 (m, 1H), 1.36 (d, J=7.0, 1H).

Example 46

2-[4-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino]-3-(2,4-dichloro-phenyl)-propionicacid

(R)-2-Amino-3-(2,4-dichloro-phenyl)-propionic acid was treated as inEXAMPLE 2, Part A, to produce(R)-2-amino-3-(2,4-dichloro-phenyl)-propionic acid methyl esterhydrochloride as a white solid. This ester was coupled with4-chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoic acid as inEXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as inEXAMPLE 2, Part E, to afford title compound. HPLC: R_(T)=10.20 min. MS(ESI−): mass calcd. for C₂₂H₁₅Cl₃F₂N₂O₅S, 563.8; m/z found, 563 [M−H]⁻.¹H NMR (400 MHz, acetone-d₆): 8.56 (d, J=8.1, 1H), 7.82 (d, J=8.6. 1H),7.77-7.71 (m, 1H), 7.70 (d, J=2.0, 1H), 7.50-7.48 (m, 2H), 7.31 (dd,J=8.3, 2.1, 1H), 7.22-7.14 (m, 3H), 5.08-5.00 (m, 1H), 3.62-3.51 (m,1H), 3.34-3.21 (m, 1H).

Example 47

N-[2-(2,4-Dichloro-phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzamide

This compound was prepared from2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoic acid and2-(2,4-dichloro-phenyl)-propylamine hydrochloride (prepared as inEXAMPLE 5, substituting 2,4-dichloro-phenyl)-acetonitrile in Part A) asin Example 1, Part C. HPLC: R_(T)=11.10 min. MS (ESI−): mass calcd. forC₂₂H₁₇Cl₂F₂IN₂O₃S, 625.3; m/z found, 624 [M−H]⁻. ¹H NMR (400 MHz,CDCl₃): 11.51 (s, 1H), 8.06 (d, J=1.6, 1H), 7.52-7.45 (m, 1H), 7.39 (d,J=1.8, 1H), 7.35 (dd, J=8.3, 1.6, 1H), 7.27 (d, J=1.9, 2H), 7.04-6.93(m, 3H), 6.09 (br m, 1H), 3.77-3.69 (m, 1H), 3.69-3.58 (m, 1H),3.57-3,47 (m, 1H), 1.31 (d, J=6.8, 3H).

Example 48

2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-N-[2-(4-nitro-phenyl)-propyl]-benzamide

This compound was prepared from2-(2,6-difluorobenzenesulfonylamino)-4-iodo-benzoic acid and2-(4-nitrophenyl)-propylamine hydrochloride (prepared as in EXAMPLE 5,substituting 4-nitro-phenyl)-acetonitrile in Part A) as in Example 1,Part C. HPLC: R_(T)=10.30 min. MS (ESI−): mass calcd. forC₂₂H₁₈F₂IN₃O₅S, 601.4; m/z found, 600 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃):8.19 (d, J=8.7, 2H), 8.05 (d, J=1.5, 1H), 7.56-7.46 (m, 1H), 7.41 (d,J=8.7, 2H), 7.33 (dd, J=8.3, 1.5, 1H), 7.00 (t, J=8.6, 2H), 6.89 (d,J=8.3, 1H), 6.13 (br m, 1H), 3.74 (td, J=12.9, 6.3, 1H), 3.51 (ddd,J=14.0, 8.5, 5.9, 1H), 3.26 (m, 1H), 1.38 (d, J=7.0, 3H).

Example 49

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-((2S,1R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-benzamide

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid wascoupled with (1S,2R)-(+)-norephedrine as in EXAMPLE 1, Part C. HPLC:R_(T)=10.13 min. MS (ESI−): mass calcd. for C₂₂H₁₉ClN₄O₄S₂, 502.05; m/zfound, 501 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.69 (s, 1H), 8.37 (dd,J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.73 (d, J=2.0, 1H), 7.72(dd, J=8.8, 7.0, 1H), 7.41-7.29 (m, 5H), 7.24 (d, J=8.4, 1H), 6.93 (dd,J=8.4, 2.0, 1H), 6.28 (br d, J=8.3, 1H), 4.98 (d, J=3.0, 1H), 4.45 (ddq,J=8.3, 6.9, 3.0, 1H), 2,60 (br s, 1H), 1.05 (d, J=6.9, 3H).

Example 50

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-indan-2-yl-benzamide

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid wascoupled with 2-aminoindane as in EXAMPLE 1, Part C. HPLC: R_(T)=10.24min. MS (ESI−): mass calcd. for C₂₂H₁₇ClN₄O₃S₂, 484.04; m/z found, 483[M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.64 (s, 1H), 8.37 (dd, J=7.0, 1.0,1H), 8.23 (dd, J=8.8, 1.0, 1H), 7.72 (dd, J=8.8, 7.0, 1H), 7.72 (d,J=2.0, 1H), 7.28-7.19 (m, 4H), 7.14 (d, J=8.4, 1H), 6.89 (dd, J=8.4,2.0, 1H), 6.12 (br d, J=7.5, 1H), 4.87-4.80 (m, 1H), 3.41 (dd, J=16.3,7.0, 2H), 2.83 (dd, J=16.3, 3.9, 2H).

Example 51

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-methyl-N-(2-pyridin-2-yl-ethyl)-benzamidehydrochloride

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid wascoupled with N-methyl-2-pyridin-2-ylethylamine as in EXAMPLE 1, Part C.The hydrochloride salt was isolated as a white solid after repeatedconcentration from methanolic HCl. HPLC: R_(T)=7.10 min. MS (ESI−): masscalcd. for C₂₁H₁₈ClN₅O₃S₂, 487.05; m/z found, 486 [M−H]⁻. ¹H NMR (500MHz, CD₃OD): rotameric broadening, 8.79 (br d, J=4.7, 1H), 8.61-8.52 (brm, 1H), 8.33 (br d, J=8.8, 1H), 8.24-8.16 (br m, 1H), 8.16-8.10 (br m,1H), 7.98-7.90 (br m, 1H), 7.82-7.75 (br m, 1H), 7.23-7.15 (br m, 1H),7.00-6.90 (br m, 1H), 3.95-3.83 (br m, 2H), 3.49-3.38 (br m, 2H), 2.92(br s, 3H).

Example 52

(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(4-chloro-phenyl)-1-hydroxymethyl-ethyl]-benzamide

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid wascoupled with (±)-2-amino-3-(4-chloro-phenyl)-propan-1-ol as in EXAMPLE1, Part C. HPLC: R_(T)=9.71 min. MS (ESI−): mass calcd. forC₂₂H₁₈Cl₂N₄O₄S₂, 536.01; m/z found, 535/537 [M−H]⁻. ¹H NMR (500 MHz,CDCl₃): 11.57 (s, 1H), 8.38 (br d, J=6.2, 1H), 8.22 (br d, J=8.4, 1H),7.71 (br m, 2H), 7.35-7.10 (br m, 5H), 6.92 (br d, J=6.0, 1H), 6.30 (brm, 1H), 4.36-4.27 (br m, 1H), 3.76-3.62 (br m, 2H), 2.98-2.85 (br m,2H), 1.92 (br s, 1H).

Example 53

(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-[2-(4-chloro-phenyl)-1-methyl-ethyl]-benzamide

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromobenzoic acid wascoupled with (±)-2-(4-chlorophenyl)-1-methylethylamine as in EXAMPLE 1,Part C. HPLC: R_(T)=10.50 min. MS (ESI−): mass calcd. forC₂₂H₁₈BrClN₄O₃S₂, 563.97; m/z found, 563/565 [M−H]⁻. ¹H NMR (400 MHz,CDCl₃): 11.61 (s, 1H), 8.37 (dd, J=7.0, 1.2, 1H), 8.22 (dd, J=8.8, 1.0,1H), 7.88 (d, J=1.8, 1H), 7.72 (dd, J=8.8, 7.0, 1H), 7.32-7.25 (m, 2H),7.13-7.05 (m, 2H), 7.07 (dd, J=8.4, 1.8, 1H), 7.01 (d, J=8.4, 1H), 5.74(br d, J=7.8, 1H), 4.40-4.28 (m, 1H), 2.88 (dd, J=13.6, 5.6, 1H), 2.75(dd, J=13.6, 7.1, 1H), 1.17 (d, J=6.7, 3H).

Example 54

(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-propyl]-4-methyl-benzamide

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-methyl-benzoic acid wascoupled with (±)-2-(4-chloro-phenyl)-propylamine as in EXAMPLE 1, PartC. HPLC: R_(T)=10.22 min. MS (ESI−): mass calcd. for C₂₃H₂₁ClN₄O₃S₂,500.07; m/z found, 499 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.48 (s, 1H),8.31 (dd, J=7.0, 1.0, 1H), 8.18 (dd, J=8.8, 1.0, 1H), 7.67 (dd, J=8.8,7.0, 1H), 7.47 (s, 1H), 7.33-7.27 (m, 2H), 7.16-7.10 (m, 2H), 6.90 (d,J=8.0, 1H), 6.71 (d, J=8.0, 1H), 5.75-5.70 (m, 1H), 3.73-3.62 (m, 1H),3.30-3.21 (m, 1H), 3.05-2.94 (m, 1H), 2.26 (s, 3H), 1.30 (d, J=7.0, 3H).

Example 55

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[(1R,2S)-2-(4-chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-benzamide

A. (R)-4-Benzyl-3-propionyl-oxazolidin-2-one. To a solution of(R)-4-benzyl-oxazolidin-2-one (3.0 g, 16.9 mmol) in THF (100 mL) at −78°C. was added n-BuLi (2.5 M hexanes, 7.1 mL, 17.8 mmol) in rapid dropsvia syringe. The solution was stirred for 20 min at −78° C. Propionylchloride (1.6 mL, 18.4 mmol) was added rapidly via syringe. The reactionsolution was allowed to warm slowly to rt overnight then was quenched bythe addition of satd. aq. NH₄Cl. The mixture was concentrated, dilutedwith water, and extracted with DCM (3×). The combined organic layerswere dried (Na₂SO₄) and concentrated to give the crude product, whichwas purified by flash chromatography (EtOAc/hexanes) to afford the titlecompound as a white solid (3.70 g, 94%). ¹H NMR (500 MHz, CDCl₃):7.36-7.31 (m, 2H), 7.30-7.25 (m, 1H), 7.23-7.19 (m, 2H), 4.71-4.64 (m,1H), 4.20 (dd, J=9.1, 7.5, 1H), 4.17 (dd, J=9.1, 3.1, 1H), 3.31 (dd,J=13.4, 3.3, 1H), 2.99 (dq, J=17.9, 7.4, 1H), 2.93 (dq, J=17.9, 7.3,1H), 2.77 (dd, J=13.4, 9.6, 1H), 1.21 (t, J=7.3, 3H).

B.(4R)-4-Benzyl-3-[(2R,3R)-3-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionyl]-oxazolidin-2-one.To a solution of (R)-4-benzyl-3-propionyl-oxazolidin-2-one (1.0 g, 4.3mmol) in dry DCM (10 mL) at 0° C. under an inert atmosphere was addedn-Bu₂BOTf (1.32 mL, 5.2 mmol) followed by Et₃N (0.78 mL, 5.6 mmol) bothin a dropwise manner via syringe while keeping the internal temperaturebelow 4° C. After 30 min at 0° C., the mixture was cooled to −65° C.,and a solution of p-chlorobenzaldehyde (661 mg, 4.7 mmol) in DCM (2 mL)was added dropwise via syringe. The resulting mixture was stirred for 1h at −65° C., then was allowed to warm to 0° C. slowly and was held at0° C. for 1 h. The reaction was quenched by the addition of 3:1 MeOH/pH7 phosphate buffer (20 mL). A 2:1 solution of MeOH/30% H₂O₂ (15 mL) wascarefully added by pipet while keeping the internal temperature below10° C. After addition was complete, the mixture was concentrated, andthe residue was poured into water and extracted with DCM (3×). Thecombined organic layers were dried (Na₂SO₄) and concentrated to give thecrude product, which was purified by flash chromatography (0 to 30% Et₂Oin 1:1 hexanes/DCM) to afford the aldol adduct as a white foam (1.32 g,82%). ¹H NMR (400 MHz, CDCl₃): 7.37-7.26 (m, 7H), 7.23-7.17 (m, 2H),5.12-5.08 (m, 1H), 4.69-4.62 (m, 1H), 4.22-4.13 (m, 2H), 4.03 (dq,J=7.0, 3.6, 1H), 3.25 (dd, J=13.4, 3.3, 1H), 3.20 (d, J=2.5, 1H), 2.79(dd, J=13.4, 9.4, 1H), 1.18 (d, J=7.0, 3H).

C. (2R,3R)-3-(4-Chloro-phenyl)-3-hydroxy-2-methyl-propionic acid. Asolution of(4R)-4-benzyl-3-[(2R,3R)-3-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionyl]-oxazolidin-2-one(1.32 g, 3.53 mmol) in 4:1 THF/water (20 mL) was cooled to 0° C. andtreated with 30% aq. H₂O₂ (1.5 mL, 13.2 mmol) and LiOH (1 M in water,5.6 mL, 5.6 mmol). The reaction mixture was stirred for 1 h at 0° C.,and then a solution of Na₂SO₃ (1.76 g, 14 mmol) in water (10 mL) wasadded. The mixture was concentrated at a temperature <30° C. The aqueouslayer was extracted with DCM (3×), then was acidified with conc. HCl andextracted with EtOAc (4×). The combined EtOAc layers were dried (Na₂SO₄)and concentrated to give the crude acid, which was used without furtherpurification (0.76 g, quant.). ¹H NMR (500 MHz, CDCl₃): 7.36-7.32 (m,2H), 7.32-7.28 (m, 2H), 5.16 (d, J=3.9, 1H), 2.81 (dq, J=7.2, 3.9, 1H),1.15 (d, J=7.2, 3H).

D.(2R,3R)-3-(tert-Butyl-dimethyl-silyloxy)-3-(4-chloro-phenyl)-2-methyl-propionicacid. A solution of(2R,3R)-3-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionic acid (0.76 g,3.5 mmol) in DCM (20 mL) was cooled to 0° C. and treated with2,6-lutidine (1.24 mL, 10.6 mmol) and tert-butyldimethylsilyltrifluoromethanesulfonate (1.9 mL, 8.27 mmol). The reaction solution wasstirred at 0° C. for 30 min then allowed to warm to rt and stir 1 h. Thereaction was quenched with 1 M HCl and the mixture was extracted withDCM (3×). The combined organic layers were dried (Na₂SO₄) andconcentrated to give the crude bis-silylated ester. The silyl ester wasstirred in MeOH (10 mL) at rt and treated with 5% aq. K₂CO₃ (5 mL). Themixture was stirred 3 h, then was concentrated, diluted with 1 N HCl,and extracted with DCM (4×). The combined organic layers were dried(Na₂SO₄) and concentrated to give the crude acid, which was used withoutfurther purification (1.06 g, 91%). ¹H NMR (400 MHz, CDCl₃): 7.32-7.27(m, 2H), 7.27-7.22 (m, 2H), 5.01 (d, J=5.3, 1H), 2.70 (dq, J=7.2, 5.6,1H), 1.11 (d, J=6.8, 3H), 0.88 (s, 9H), 0.03 (s, 3H), −0.18 (s, 3H).

E.(1R,2S)-[2-(tert-Butyl-dimethyl-silyloxy)-2-(4-chloro-phenyl)-1-methyl-ethyl]-carbamicacid tert-butyl ester. To a solution of(2R,3R)-3-tert-butyl-dimethyl-silyloxy)-3-(4-chloro-phenyl)-2-methyl-propionicacid 0.93 g, 2.8 mmol) in THF (30 mL) at 0° C. was added Et₃N (0.438 mL,3.1 mmol) followed by ethyl chloroformate 0.30 mL, 3.1 mmol). Thesolution was stirred for 1 h at 0° C., and a solution of NaN₃ (552 mg,8.5 mmol) in water (10 mL) was added. The reaction solution was stirredfor 4 h with warming to rt. The mixture was poured into water andextracted with Et₂O (3×). The combined organic extracts were dried(MgSO₄) and concentrated to afford the crude acyl azide. A mixture ofthe acyl azide, tert-butanol (10 mL), and toluene (20 mL) was heated atreflux for 12 h. The reaction mixture was cooled and concentrated, andthe residue was purified by flash chromatography (EtOAc/hexanes) toprovide the desired product as a colorless oil (354 mg, 31%). ¹H NMR(400 MHz, CDCl₃): 7.28 (s, 4H), 4.90 (br s, 1H), 4.60 (br d, J=8.0, 1H),3.77-3.65 (m, 1H), 1.46 (s, 9H), 0.94 (s, 9H), 0.88 (d, J=6.8, 3H), 0.06(s, 3H), −0.13 (s, 3H).

F. (1S,2R)-2-Amino-1-(4-chloro-phenyl)-propan-1-ol hydrochloride. Asolution of(1R,2S)-[2-(tert-butyl-dimethyl-silyloxy)-2-(4-chloro-phenyl)-1-methyl-ethyl]-carbamicacid tert-butyl ester (354 mg, 0.88 mmol) in MeOH (10 mL) at rt wastreated with HCl (4 M in dioxane, 3 mL). After 1 h, the mixture wasconcentrated to provide the desired amine as the hydrochloride salt (200mg, quant.). ¹H NMR (400 MHz, CD₃OD): 7.43-7.37 (m, 4H), 4.91 (d, J=3.4,1H), 3.50 (dq, J=6.8, 3.5, 1H), 1.07 (d, J=6.8, 3H).

G. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[(1R,2S)-2-(4-chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-benzamide.2-(Benzo[1,2,5]-thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid wascoupled with (1S,2R)-2-amino-1-(4-chloro-phenyl)-propan-1-olhydrochloride as in EXAMPLE 1, Part C. HPLC: R_(T)=10.17 min. MS (ESI−):mass-calcd. for C₂₂H₁₈Cl₂N₄O₄S₂, 536.01; m/z found, 535/537 [M−H]⁻. ¹HNMR (400 MHz, CDCl₃): 11.64 (s, 1H), 8.39 (dd, J=7.0, 1.0, 1H), 8.23(dd, J=8.8, 1.0, 1H), 7.73 (dd, J=8.8, 7.0, 1H), 7.72 (d, J=2.0, 1H),7.38-7.33 (m, 2H), 7.33-7.28 (m, 2H), 7.24 (d, J=8.5, 1H), 6.95 (dd,J=8.4, 2.0, 1H), 6.22 (br d, J=8.1, 1H), 4.97 (d, J=2.9, 1H), 4.42 (ddq,J=8.3, 7.0, 2.9, 1H), 1.04 (d, J=6.9, 3H).

Example 56

(2S,3R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-butyricacid

A. 3,4-Dichlorocinnamyl alcohol. To a stirred suspension of3,4-dichlorocinnamic acid (25.39 g, 117 mmol) in THF (117 mL) at rt wasadded Et₃N (16.7 mL, 120 mmol). The resulting mixture was cooled in anice bath and treated with ethyl chloroformate (11.5 mL, 120 mmol) whilekeeping the internal temperature below 10° C. The resulting thicksuspension was stirred rapidly for 1 h in an ice bath. The mixture wasfiltered through a sintered glass funnel, washing with THF. The filtratewas concentrated to afford the mixed carbonate. The crude carbonate wasstirred in MeOH (71 mL) at rt as NaBH₄ (16.82 g, 445 mmol) was added inportions while maintaining the internal temperature below 45° C. Themixture was stirred overnight. The mixture was concentrated, dilutedwith DCM, and washed with 1 N NaOH (2×). The organic layer was dried(Na₂SO₄) and concentrated to afford a white solid, which wasrecrystallized (EtOAc/hexanes) to afford 3 crops of the desired cinnamylalcohol totaling 15.9 g (67%, 96% purity by ¹H NMR). ¹H NMR (400 MHz,CDCl₃): 7.46 (d, J=2.1, 1H), 7.38 (d, J=8.3, 1H), 7.20(dd, J=8.4, 2.1,1H), 6.54 (dt, J=15.9, 1.5, 1H), 6.36 (dt, J=15.9, 5.3, 1H), 4.34 (ddd,J=5.8, 5.3, 1.5, 2H), 1.51 (t, J=5.8, 1H).

B. (2S-trans)-[3-(3,4-Dichloro-phenyl)-oxiranyl]-methanol. To asuspension of powdered 4 Å molecular sieves (3.2 g) in DCM (144 mL) wasadded Ti(O-iPr)₄ (0.864 mL, 2.93 mmol), (+)-L-diisopropyl tartrate(0.924 mL, 4.39 mmol), and t-BuOOH (5.5 M in decane, 10.8 mL, 59.4mmol). The mixture was cooled to −20° C. stirred for 1 h. A solution of3,4-dichlorocinnamyl alcohol (6.0 g, 29.5 mmol) in DCM (30 mL) was addedvia cannula. After 18 h at −20° C., the reaction was quenched byaddition of 10% aq. NaOH and brine (10%, 4 mL). The cooling bath wasremoved, and after stirring for 20 min, Et₂O (30 mL) was added followedby MgSO₄ (8 g) and diatomaceous earth (8 g). The mixture was stirredrapidly for 15 min then was filtered through a pad of diatomaceousearth, washing with excess Et₂O. The filtrate was concentrated, and thedesired epoxide was crystallized from the yellow residue with a warmDCM/hexanes mixture to afford 4.22 g (65%) of pale yellow crystals. Theepoxide was determined to be >95%.ee by ¹H NMR analysis of both the R-and S-Mosher ester derivatives. ¹H NMR (400 MHz, CDCl₃): 7.42 (d, J=8.3,1H), 7.37 (d, J=2.0, 1H), 7.13 (dd, J=8.3, 2.0, 1H), 4.04 (dd, J=12.9,2.2, 1H), 3.91 d, J=2.0, 1H), 3.82 (dd, J=12.9, 3.4, 1H), 3.18-3.11 (m,1H), 1.80 (br s, 1H).

C. (2R,3R)-3-(3,4-Dichloro-phenyl)-butane-1,2-diol. To a slurry of CuCN(5.20 g, 58.1 mmol) in dry Et₂O (300 mL) under an inert atmosphere at−78° C. was added MeLi (1.6 M in Et₂O, 73 mL, 117 mmol). A yellowprecipitate formed, and the mixture was allowed to stir untilhomogeneous (1 h). A solution of(2S-trans)-[3-(3,4-dichloro-phenyl)-oxiranyl]-methanol (4.22 g, 19.3mmol) in Et₂O (80 mL) was added dropwise via cannula over 40 min. Themixture was stirred for 1 h at −78° C., then was allowed to warm to 0°C. over 2 h. The reaction was quenched by careful addition of satd. aq.NH₄Cl (160 mL) causing vigorous gas evolution and precipitation of awhite and yellow solid. Concentrated NH₄OH (33% NH₃, 20 mL) was added,and the mixture was stirred vigorously for 10 min. The biphasic mixturewas separated, and the aqueous layer was extracted with Et₂O (3×). Thecombined organic layers were dried (MgSO₄) and concentrated. The residuewas purified by flash chromatography (EtOAc/hexanes) to afford the diolas a colorless viscous liquid (3.40 g, 75%). ¹H NMR (400 MHz, CDCl₃):7.40 (d, J=8.3, 1H), 7.36 (d, J=2.1, 1H), 7.10 (dd, J=8.4, 2.2, 1H),3.81-3.71 (m, 2H), 3.57-3,47 (m, 1H), 2.84 (quint, J=7.2, 1H), 3.18-3.11(m, 1H), 1.96 (br s, 1H), 1.89 (br s, 1H), 1.26 (d, J=7.1, 3H).

D.(2R,3R)-1-(tert-Butyl-dimethyl-silyloxy)-3-(3,4-dichloro-phenyl)-butan-2-ol.To a stirred solution of (2R,3R)-3-(3,4-dichloro-phenyl)-butane-1,2-diol(3.20 g, 13.6 mmol) and imidazole (1.39 g, 20.4 mmol) in DCM (28 mL) atrt was added tert-butyldimethylsilyl chloride (TBSCl; 2.15 g, 14.3mmol). The solution was stirred for 1 h then quenched by addition ofsatd. aq. NH₄Cl (100 mL). The mixture was stirred for 5 min, the layerswere separated, and the aqueous layer was extracted with DCM (3×). Thecombined organic layers were dried (Na₂SO₄) and concentrated to yield aviscous yellow liquid. The product was purified by flash chromatography(EtOAc/hexanes) to afford 4.52 g (95%) of the desired product as acolorless viscous liquid. ¹H NMR (400 MHz, CDCl₃): 7.37 (d, J=8.3, 1H),7.36 (d, J=2.1, 1H), 7.10 (dd, J=8.2, 2.1, 1H), 3.75-3.68 (m, 1H), 3.65(dd, J=9.9, 3.8, 1H), 3.45 (dd, J=9.9, 7.1, 1H), 2.81 (quint, J=7.0,1H), 2.37 (d, J=4.0, 1H), 1.25 (d, J=7.2, 3H), 0.89 (s, 9H), 0.07 (s,3H), 0.06 (s, 3H).

E.(2R,3R)-1-(tert-Butyl-dimethyl-silyloxy)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butane.To a solution of(2R,3R)-1-(tert-butyl-dimethyl-silyloxy)-3-(3,4-dichloro-phenyl)-butan-2-ol(4.63 g, 13.2 mmol) in DCM (44 mL) at 0° C. were added Et₃N (4.6 mL,33.0 mmol), DMAP (81.0 mg, 0.7 mmol), and MsCl (2.2 ml, 28.4 mmol). Themixture was stirred overnight at rt. The reaction was quenched withwater (100 mL) and extracted with DCM (3×). The combined organic layerswere dried (Na₂SO₄) and concentrated to yield an orange oil. The productwas purified by flash chromatography (Et₂O/hexanes) to afford 4.99 g(88%) of the desired product as a colorless liquid. ¹H NMR (400 MHz,CDCl₃): 7.39 (d, J=8.3, 1H), 7.35 (d, J=2.1, 1H), 7.12 (dd, J=8.3, 2.1,1H), 4.72-4.69 (m, 1H), 3.71 (dd, J=11.4, 5.7, 1H), 3.64 (dd, J=11.4,4.3, 1H), 3.24-3.18 (m, 1H), 2.81 (s, 3H), 1.36 (d, J=7.2, 3H), 0.90 (s,9H), 0.06 (s, 3H), 0.06 (s, 3H).

F. (2R,3R)-3-(3,4-Dichloro-phenyl)-2-methanesulfonyloxy-butan-1-ol. To asolution of(2R,3R)-1-(tert-butyl-dimethyl-silyloxy)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butane(4.99 g, 11.7 mmol) in THF (117 mL) at 0° C. was addedtetrabutylammonium fluoride (TBAF; 1.0 M in THF, 23.4 mL). The solutionwas stirred at 0° C. for 15 min, then was diluted with 1 N HCl (100 ml)and extracted with DCM (3×). The combined organic layers were dried(Na₂SO₄) and concentrated to yield a yellow oil. The product waspurified by flash chromatography (EtOAc/hexanes) to give 3.45 g (94%) ofthe desired product. ¹H NMR (400 MHz, CDCl₃): 7.41 (d, J=8.0, 1H), 7.35(d, J=2.0, 1H), 7.12 (dd, J=8.2, 2,4, 1H), 4.82-4.78 (m, 1H), 3.88-3.84(m, 1H), 3.74-3.69 (m, 1H), 3.17 (q, J=7.1, 1H), 2.78 (s, 3H), 1.98 (brs, 1H), 1.36 (d, J=7.2, 3H).

G. (2R,3R)-3-(3,4-Dichloro-phenyl)-2-methanesulfonyloxy-butyric acidmethyl ester. Jones reagent was prepared by mixing chromium (VI) oxide(2.87 g, 28.7 mmol), sulfuric acid (2.44 mL), and water (9.5 mL) for 10min. The solution was used directly, and was added dropwise to asolution of(2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butan-1-ol (1.50 g,4.79 mmol) in acetone (100 mL). After 4 h, isopropanol (9 mL) was addedand the mixture was concentrated. Water was added, and the aqueous layerwas extracted with DCM (3×). The combined organic layers were washedwith brine, dried (MgSO₄), and concentrated to give the crude acid. To asolution of (2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butyricacid (1.57 g, 4.80 mmol) in DMF (20 mL) were added KHCO₃ (1.44 g, 14.4mmol) and Mel (0.90 mL, 14.4 mmol). After 12 h, the mixture was dilutedwith water and extracted with EtOAc (2×), and the combined organicphases were washed with brine, dried (MgSO₄) and concentrated. Theproduct was purified by flash chromatography to give 1.13 g (69% over 2steps) of the desired product. ¹H NMR (400 MHz, CDCb₃): 7.38 (d, J=8.3,1H), 7.31 (d, J=2.1, 1H), 7.08 (dd, J=8.3, 2.1, 1H), 5.14 (d, J=4.7,1H), 3.73 (s, 3H), 3.47-3.43 (m, 1H), 3.07 (s, 3H), 1.43 (d, J=7.2, 3H).

H. (2S,3R)-2-Azido-3-(3,4-dichloro-Phenyl)-butyric acid methyl ester. Toa solution of(2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butyric acid methylester (0.70 g, 2.05 mmol) in DMF (10 mL) was added NaN₃(0.27 g, 4.10mmol). The reaction was heated at 55° C. overnight. The mixture wasquenched with water and extracted with EtOAc. The organic phase waswashed with water (2×), dried (MgSO₄), and concentrated. The product waspurified by flash chromatography to give 0.42 g (71%) of product. ¹H NMR(500 MHz, CDCl₃): 7.39 (d, J=8.3, 1H), 7.35 (d, J=2.1, 1H), 7.10 (dd,J=8.3, 2.1, 1H), 3.96 (d, J=6.4, 1H), 3.71 (s, 3H), 3.29 (m, 1H), 1.33(d, J=7.0, 3H).

I. (2S,3R)-2-Amino-3-(3,4-dichloro-phenyl)-butyric acid methyl ester. Toa solution of (2S,3R)-2-azido-3-(3,4-dichloro-phenyl)-butyric acidmethyl ester (0.42 g, 1.46 mmol) in EtOAc (30 mL) was added Lindlar'scatalyst. The mixture was hydrogenated at 50 psi. After 16 h, thereaction mixture was filtered through SiO₂ and concentrated to afford0.28 g (74%) of the desired product. ¹H NMR (500 MHz, CDCl₃): 7.39 (d,J=8.3, 1H), 7.35 (d, J=2.1, 1H), 7.10 (dd, J=8.3, 2.1, 1H), 3.96 (d,J=6.4, 1H), 3.71 (s, 3H), 3.31-3.27 (m, 1H), 1.33 (d, J=7.0, 3H).

J.(2S,3R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-butyricacid. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acidwas coupled to (2S,3R)-2-amino-3-(3,4-dichloro-phenyl)-butyric acidmethyl ester as in EXAMPLE 1, Part C. The resulting methyl ester washydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC:R_(T)=10.22 min. MS (ESI−): mass calcd. for C₂₃H₁₇Cl₃N₄O₅S₂, 597.97; m/zfound, 597/599 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.26 (s, 1H), 8.36 (d,J=7.0, 1H), 8.21 (d, J=8.8, 1H), 7.73-7.70 (m, 2H), 7.37 (d, J=8.3, 1H),7.27 (m, 1H), 7.23 (d, J=6.4, 1H), 7.04 (dd, J=8.2, 2.0, 1H), 6.96 (dd,J=8.4, 2.0, 1H), 6.44 (d, J=8.6, 1H), 4.97-4.94 (m, 1H), 3.38-3.36 (m,1H), 1.46 (d, J=7.2, 3H).

Example 57

(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide

The title compound was prepared from2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid and(÷)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1,Part C. HPLC: R_(T)=11.97 min. MS (ESI−): mass calcd. forC₂₂H₁₇Cl₃N₄O₃S₂, 553.98; m/z found, 553/555/557 [M−H]⁻. ¹H NMR (400 MHz,CDCl11.51 (s, 1H), 8.36 (dd, J=7.0, 1.1, 1H), 8.22 (dd, J=8.8, 1.0, 1H),7.74-7.70 (m, 2H), 7.40 (d, J=8.2, 1H), 7.29 (d, J=2.1, 1H), 7.04 (dd,J=8.3, 2.1, 1H), 7.01-6.99 (m, 1H), 6.89 (dd, J=8.4, 2.0, 1H), 5.81 (s,1H), 3.74-3.67 (m, 1H), 3.34-328 (m, 1H), 3.06-2.98 (m, 1H), 1.30 (d,J=7.0, 3H).

Example 58

(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide

The title compound was prepared from2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acidand (±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE1, Part C. HPLC: R_(T)=12.51 min. MS (ESI−): mass calcd. forC₂₂H₁₆Cl₄N₄O₃S₂, 587.94; m/z found, 587/589/591 [M−H]⁻. ¹H NMR (500 MHz,CDCl₃): 11.22 (s, 1H), 8.35 (d, J=7.0, 1H), 8.24 (d, J=8.8, 1H), 7.89(s, 1H), 7.74-7.71 (m, 1H), 7.41 (d, J=8.2, 1H), 7.29 (d, J=2.0, 1H),7.14 (s, 1H), 7.05 (dd, J=8.2, 2.0, 1H), 5.79 (s, 1H), 3.69-3.63 (m,1H), 3.34-3.29 (m, 1H), 3.03-2.99 (m, 1H), 1.31 (d, J=7.0, 3H).

Example 59

(±)-4-Chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-2-(quinoxaline-5-sulfonylamino)-benzamide

The title compound was prepared from4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid and(±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1,Part C. HPLC: R_(T)=10.78 min. MS (ESI+): mass calcd. forC₂₄H₁₉Cl₃N₄O₃S, 548.02; m/z found, 551/553 [M+H]⁺, m/z found, 571/575[M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): 11.21 (s, 1H), 9.04 (d, J=1.7, 1H),8.96 (d, J=1.7, 1H), 8.57 (dd, J=7.3, 1.3, 1H), 8.33 (dd, J=8.5, 1.2,1H), 7.91-7.87 (m, 1H), 7.71 (d, J=1.9, 1H), 7.39 (d, J=8.2, 1H), 7.29(d, J=2.0, 1H), 7.04 (dd, J=8.2, 2.0, 1H), 6.99 (d, J=8.4, 1H), 6.88(dd, J=8.4, 2.0, 1H), 5.82 (s, 1H), 3.70-3.63 (m, 1H), 3.33-3.26 (m,1H), 3.02-2.98 (m, 1H), 1.30 (d, J=7.0, 3H).

Example 60

(R)-3-(3,4-Dichloro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid

(R)-2-(tert-Butoxycarbonylamino)-3-(3,4-dichloro-phenyl)-propionic acidwas treated as in EXAMPLE 2, Part A, to produce(R)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl esterhydrochloride as a white solid. This ester was coupled to4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1,Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, PartE, to afford the title compound. HPLC: R_(T)=10.06 min. MS (ESI−): masscalcd. for C₂₄H₁₇Cl₂IN₄O₅S, 669.93; m/z found, 669/671 [M−H]⁻. ¹H NMR(500 MHz, CDCl₃): 10.85 (s, 1H), 9.00,(d, J=1.8, 1H), 8.92 (d, J=1.7,1H), 8.54 (dd, J=7.4, 1.2, 1H), 8.33-8.31 (m, 1H), 8.07 (d, J=1.5, 1H),7.91-7.87 (m, 1H), 7.47-7.22 (m, 3H), 6.98 (dd, J=8.2, 2.0, 1H), 6.87(d, J=8.3, 1H), 6.37 (d, J=7.7, 1H), 4.92-4.88 (m, 1H), 3.23 (dd,J=14.2, 5.9, 1H), 3.14 (dd, J=14.1, 6.1, 1H).

Example 61

(±)-N-[2-(3,4-Dichloro-phenyl)-propyl]-4-iodo-2-(quinoxaline-5-sulfonylamino)-benzamide

The title compound was prepared from4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid and(±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1,Part C. HPLC: R_(T)=10.97 min. MS (ESI+): mass calcd. forC₂₄H₁₉Cl₂IN₄O₃S, 639.96; m/z found, 641/643 [M+H]⁺, m/z found, 663/665[M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): 11.07 (s, 1H), 9.03 (d, J=1.8, 1H),8.95 (d, J=1.8, 1H), 8.56 (dd, J=7.4, 1.4, 1H), 8.33 (dd, J=8.5, 1.4,1H), 8.05 (d, J=1.6, 1H), 7.91-7.87 (m, 1H), 7.39 (d, J=8.2, 1H),7.28-7.24 (m, 2H), 7.02 (dd, J=8.3, 2.1, 1H), 6.75 (d, J=8.2, 1H), 5.81(s, 1H), 3.68-3.61 (m, 1H), 3.31-3.24 (m, 1H), 3.00-2.95 (m, 1H), 1.29(d, J=7.0, 3H).

Example 62

(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoylamino]-3-(4-chloro-phenyl)-propionicacid

(R)-2-(tert-Butoxycarbonylamino)-3-(4-chloro-phenyl)-propionic acid wastreated as in EXAMPLE 2, Part A, to produce(R)-2-amino-3-4-chloro-phenyl)-propionic acid methyl ester hydrochlorideas a white solid. This ester was coupled with2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoic acid as inEXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as inEXAMPLE 2, Part E, to afford the title compound. HPLC: R_(T)=10.28 min.MS (ESI−): mass calcd. for C₂₂H₁₆Cl₂N₄O₅S₂, 549.99; m/z found, 549/551[M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 10.92 (s, 1H), 8.30 (d, J=7.0, 1H),8.19 (d, J=8.8, 1H), 7.70-7.66 (m, 1H), 7.64 (d, J=9.0, 1H), 7.31-7.26(m, 3H), 7.14 (d, J=2.3, 1H), 7.08 (d, J=8.3, 2H), 6.38 (d, J=7.3, 1H),5.00-4.96 (m, 1H), 3.29 (dd, J=14.3, 5.7, 1H), 3.20(dd, J=14.2, 5.8,1H).

Example 63

(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(3-cyano-phenyl)-propionicacid

(S)-2-(tert-Butoxycarbonylamino)-3-(3-cyano-phenyl)-propionic acid wastreated as in EXAMPLE 2, Part A, to produce(S)-2-amino-3-(3-cyano-phenyl)-propionic acid methyl ester hydrochlorideas a white solid. This ester was coupled to4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1,Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, PartE, to afford the title compound. HPLC: R_(T)=8.94 min. MS (ESI−): masscalcd. for C₂₅H₁₈ClN₅O₅S, 535.07; m/z found, 534/536 [M−H]⁻. ¹H NMR (500MHz, CDCl₃): 11.01 (s, 1H), 9.03 (d, J=1.7, 1H), 8.94 (d, J=1.7, 1H),8.57 (d, J=7.4, 1H), 8.33 (d, J=8.5, 1H), 7.90 (t, 7.5, 1H), 7.74 (d,J=1.9, 1H), 7.57-7.55 (m, 1H), 7.47-7.41 (m, 3H), 7.12 (d, J=8.4, 1H),6.93 (dd, J=5.6, 1.9, 1H), 6.40 (d, J=7.3, 1H), 5.02-4.98 (m, 1H), 3.36(dd, J=14.1, 6.0, 1H), 3.25 (dd, J=14.2, 5.6, 1H).

Example 64

(S)-3-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-4-(3,4-dichloro-phenyl)-butyricacid

(S)-3-(tert-Butoxycarbonylamino)-4-(3,4-dichloro-phenyl)-butyric acidwas treated as in EXAMPLE 2, Part A, to produce(S)-3-amino-4-(3,4-dichloro-phenyl)-butyric acid methyl esterhydrochloride as a white solid. This ester was coupled to4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1,Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, PartE. HPLC: R_(T)=9.78 min. MS (ESI−): mass calcd. for C₂₅H₁₉Cl₃N₄O₅S,592.01; m/z found; 593/595 [M−H]⁻. ¹H NMR (500 MHz, CD₃OD): 8.97 (d,J=1.8, 1H), 8.93 (d, J=1.8, 1H), 8.55 (dd, J=7.4, 1.3, 1H), 8.33 (dd,J=8.5, 1.3, 1H), 7.97-7.94 (m, 1H), 7.69 (d, J=2.0, 1H), 7.42 (d, J=8.2,1H), 7.38-7.36 (m, 2H), 7.16 (dd, J=8.2, 2.0, 1H), 6.97 (dd, J=8.6, 2.0,1H), 4.56-4.50 (m, 1H), 2.90 (dd, J=13.7, 6.1, 1H), 2.81 (dd, J=13.7,7.7, 1H), 2.54 (dd, J=15.9, 6.2, 1H), 2,45 (dd, J=15.9, 7.4, 1H).

Example 65

(S)-3-Benzo[b]thiophen-3-yl-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester

3-Benzo[b]thiophen-3-yl-2-(tert-butoxycarbonylamino)-propionic acid wastreated as in EXAMPLE 2, Part A, to produce(S)-2-amino-3-benzo[b]thiophen-3-yl-propionic acid methyl esterhydrochloride as a white solid. This ester was coupled to4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1,Part C, to afford the title compound. HPLC: R_(T)=10.33 min. MS (ESI−):mass calcd. for C₂₇H₂₁ClN₄O₅S₂, 580.06; m/z found, 579/581 [M−H]⁻. ¹HNMR (400 MHz, CDCl₃): 11.35 (s, 1H), 8.94 (d, J=1.8, 1H), 8.85 (d,J=1.8, 1H), 8.58 (dd, J=7.3, 1.4, 1H), 8.31 (dd, J=8.5, 1.3, 1H),7.90-7.86 (m, 2H), 7.77 (d, J=2.0, 1H), 7.72-7.70 (m, 1H), 7.37-7.26 (m,2H), 7.09 (s, 1H), 7.00 (d, J=8.4, 1H), 6.83 (dd, J=8.4, 2.0, 1H), 6.45(d, J=7.1, 1H), 5.09-5.05 (m, 1H), 3.77 (s, 3H), 3.53 (dd, J=14.7, 5.8,1H), 3.45 (dd, J=14.8, 5.2, 1H).

Example 66

(S)-3-Benzo[b]thiophen-3-yl-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid

(S)-3-Benzo[b]thiophen-3-yl-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester was hydrolyzed as in EXAMPLE 2, Part E. HPLC:R_(T)=9.67 min. MS (ESI−): mass calcd. for C₂₆H₁₉ClN₄O₅S₂, 566.05; m/zfound, 565/567 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.09 (s, 1H), 8.96 (d,J=1.8, 1H), 8.84 (d, J=1.8, 1H), 8.54 (dd, J=7.4, 1.3, 1H), 8.28 (dd,J=8.5, 1.3, 1H), 7.87-7.84 (m, 2H), 7.75-7.74 (m, 2H), 7.36-7.33 (m,2H), 7.21 (s, 1H), 6.89 (d, J=8.4, 1H), 6.80 (dd, J=8.4, 2.0, 1H), 6.35(d, J=7.2, 1H), 5.06 (m, 1H), 3.58 (dd, J=15.0, 5.5, 1H), 3,47 (dd,J=15.0, 6.0, 1H).

Example 67

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionicacid methyl ester

(S)-2-(tert-Butoxycarbonylamino)-3-4-chloro-phenyl)-propionic acid wastreated as in EXAMPLE 2, Part A, to produce(S)-2-amino-3-(4-chloro-phenyl)-propionic acid methyl esterhydrochloride as a white solid. This ester was coupled to2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid asin EXAMPLE 1, Part C, to afford the title compound. HPLC: R_(T)=11.61min. MS (ESI−): mass calcd. for C₂₃H₁₇Cl₃N₄O₅S₂, 597.97; m/z found,597/599 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.20 (s, 1H), 8.36 (d, J=6.3,1H), 8.23 (d, J=8.7, 1H), 7.87 (s, 1H), 7.74-7.71 (m, 1H), 7.27-7.25 (m,3H), 6.98 (d, J=8.3, 2H), 6.38 (d, J=7.3, 1H), 4.96-4.92 (m, 1H), 3.82(s, 3H), 3.23-3.14 (m, 2H).

Example 68

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionicacid

(S)-2-[2-(Benzo[12,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionicacid methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford thetitle compound. HPLC: R_(T)=10.34 min. MS (ESI−): mass calcd. forC₂₂H₁₅Cl₃N₄O₅S₂, 583.95; m/z found, 583/585 [M−H]⁻. ¹H NMR (500 MHz,CDCl₃): 11.07 (s, 1H), 8.34 (d, J=7.9, 1H), 8.22 (d, J=8.8, 1H), 7.83(s, 1H), 7.74-7.71 (m, 1H), 7.28-7.24 (m, 3H), 7.07 (d, J=8.3, 2H), 6.38(d, J=7.2, 1H), 5.01-4.97 (m, 1H), 3.30 (dd, J=14.2, 5.7, 1H), 3.21 (dd,J=14.2, 5.8, 1H).

Examples 69-93 were prepared as described in the preceding examples.Satisfactory analytical data was obtained for each compound.

Example 69

(R)-2-[4-Chloro-2-(2,4-difluoro-benzenesulfonylamino)-benzoylamino]-3-(4-chloro-phenyl)-propionicacid methyl ester

MS (ESI−): mass calcd. for C₂₃H₁₈Cl₂F₂N₂O₅S, 542.03; m/z found, 541/543[M−H]⁻.

Example 70

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(2,4-dichloro-phenyl)-ethyl]-benzamide

MS (ESI−): mass calcd. for C₂₁H₁₅Cl₃N₄O₃S₂, 539.97; m/z found, 539/541[M−H]⁻.

Example 71

(S)-2-[4-Chloro-2-(2,4-difluoro-benzenesulfonylamino)-benzoylamino]-3-(4-chloro-phenyl)-propionicacid methyl ester

MS (ESI−): mass calcd. for C₂₃H₁₈C_(l2)F₂N₂O₅S, 542.03; m/z found,541/543 [M−H]⁻.

Example 72

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-propyl]-4-iodo-benzamide

MS (ESI−): mass calcd. for C₂₂H₁₈ClIN₄O₃S₂, 611.96; m/z found, 611/613[M−H]⁻.

Example 73

(R)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-(2-hydroxy-1-methyl-1-2,2-diphenyl-ethyl)-benzamide

MS (ESI−): mass calcd. for C₂₈H₂₃ClN₄O₄S₂, 578.08; m/z found, 577/579[M−H]⁻.

Example 74

(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-(2-hydroxy-1-methyl-2,2-diphenyl-ethyl)-benzamide

MS (ESI−): mass calcd. for C₂₈H₂₃ClN₄O₄S₂, 578.08; m/z found, 577/579[M−H]⁻.

Example 75

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(2,4-dichloro-phenyl)-ethyl]-benzamide

MS (ESI−): mass calcd. for C₂₁H₁₆Cl₂N₄O₃S₂, 506.00; m/z found, 505/507[M−H]⁻.

Example 76

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(4-fluoro-phenyl)-propionicacid

MS (ESI−): mass calcd. for C₂₂H₁₆ClFN₄O₅S₂, 534.02; m/z found, 533/535[M−H]⁻.

Example 77

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-thiophen-3-yl-propionicacid

MS (ESI−): mass calcd. for C₂₀H₁₅ClN₄O₅S₃, 521.99; m/z found, 521/523[M−H]⁻.

Example 78

(S)-3-(3-Chloro-phenyl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid

MS (ESI−): mass calcd. for C₂₄H₁₈Cl₂N₄O₅S, 544.04; m/z found, 543/545[M−H]⁻.

Example 79

(S)-2-[4-Iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-p-tolyl-propionicacid

MS (ESI−): mass calcd. for C₂₅H₂₁IN₄O₅S, 616.03; m/z found, 615 [M−H]⁻.

Example 80

N-[2-(4-Bromo-phenyl)-ethyl]-4-chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzamide

MS (ESI−): mass calcd. for C₂₁H₁₆BrClF₂N₂O₃S, 527.97; m/z found, 527/529[M−H]⁻.

Example 81

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-6-chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide

MS (ESI−): mass calcd. for C₂₂H₁₇Cl₃N₄O₃S₂, 553.98; m/z found, 553/555[M−H]⁻.

Example 82

(R)-3-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-4-(3,4-dichloro-phenyl)-butyricacid

MS (ESI−): mass calcd. for C₂₅H₁₉Cl₃N₄O₅S, 592.01; m/z found, 591/593[M−H]⁻.

Example 83

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoylamino]-3-(4-chloro-phenyl)-propionicacid

MS (ESI−): mass calcd. for C₂₂H₁₆Cl₂N₄O₅S₂, 549.99; m/z found, 549/551[M−H]⁻.

Example 84

(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(3-nitro-phenyl)-propionicacid

MS (ESI−): mass calcd. for C₂₄H₁₈ClN₅O₇S, 555.06; m/z found, 554/556[M−H]⁻.

Example 85

(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(3,4-difluoro-phenyl)-propionicacid

MS (ESI−): mass calcd. for C₂₄H₁₇ClF₂N₄O₅S, 546.06; m/z found, 545/547[M−H]⁻.

Example 86

(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(4-cyano-phenyl)-propionicacid

MS (ESI−): mass calcd. for C₂₅H₁₈ClN₅O₅S, 535.07; m/z found, 534/536[M−H]⁻.

Example 87

(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-thiophen-3-yl-propionicacid

MS (ESI−): mass calcd. for C₂₂H₁₇ClN₄O₅S₂, 516.03; m/z found, 515/517[M−H]⁻.

Example 88

(S)-4-(4-Chloro-phenyl)-3-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-butyricacid methyl ester

MS (ESI+): mass calcd. for C₂₆H₂₂Cl₂N₄O₅S, 572.07; m/z found, 573/575[M+H]⁺, 595/597 [M+Na]⁺.

Example 89

(S)-4-(4-Chloro-phenyl)-3-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-butyricacid

MS (ESI−): mass calcd. for C₂₅H₂₀Cl₂N₄O₅S, 558.05; m/z found, 557/559[M−H]⁻.

Example 90

(S)-3-(4-Chloro-phenyl)-2-[4-iodo2-(quinoxaline-,5-sulfonylamino)-benzoylamino]-propionic acid

MS (ESI−): mass calcd. for C₂₄H₁₈ClIN₄O₅S, 635.97; m/z found, 635/637[M−H]⁻.

Example 91

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo4benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid

HPLC: R_(T)=10.22 min. MS (ESI−): mass calcd. for C₂₂H₅BrClIN₄O₅S₂,721.77; m/z found, 719/721 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.09 (s,1H), 8.31 (d, J=7.0, 1H), 8.19 (d, J=8.8, 1H), 8.02 (s, 1H), 7.71 (dd,J=8.7, 7.1, 1H), 7.39(d, J=1.7, 1H), 7.34 (d, J=8.2, 1H), 7.31-7.25 (m,1H), 7.02 (dd, J=8.2, 1.5, 1H), 6.89 (d, J=8.3, 1H), 6.50 (br s, 1H),4.95 (q, J=5.8, 1H), 3.32-3.13 (m, 2H).

Example 92

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-3-iodo-phenyl)-propionicacid

HPLC: R_(T)=10.24 min. MS (ESI−): mass calcd. for C₂₂H₁₅ClI₂N₄O₅S₂,768.77; m/z found, 767/769 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.16(s,1H), 8.35 (d, J=6.9, 1H), 8.22 (d, J=8.8, 1H), 8.10-8.06 (m, 1H),7.73 (dd, J=8.6, 7.3, 1H), 7.65-7.63 (m, 1H), 7.38-7.30 (m, 2H),7.10-7.05 (m, 1H), 6.92 (d, J=8.3, 1H), 6.43 (d, J=7.2, 1H), 4.95 (q,J=5.5, 1H), 3.30-3.12 (m, 2H).

Example 93

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid

HPLC: R_(T)=10.92 min. MS (ESI−): mass calcd. for C₂₂H₁₅BrFIN₄O₅S₂,705.32; m/z found, 703/705 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.16 (s, 1H), 8.34 (dd, J=7.0, 0.9, 1H), 8.20 (dd, J=8.8, 0.9, 1H), 8.04 (d,J=1.5, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.32 (dd, J=6.5, 1.8, 1H), 7.29(dd, J=8.2, 1.6, 1H), 7.09-6.99 (m, 2H), 6.89 (d, J=8.3, 1H), 6.45 (d,J=7.1, 1H), 4.96 (q, J=5.7, 1H.), 3.31-3.14 (m, 2H).

Example 94

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionicacid

A.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionicacid methyl ester. The title compound (49 mg, 84%) was prepared from2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid (Example101, Part D) and (S)-2-amino-3,3-bis-(4-chloro-phenyl)-propionic acidmethyl ester (Example 106, Part H) as in Example 1, Part C. ¹H NMR (500MHz, CDCl₃): 11.16 (s, 1H), 8.36 (dd, J=7.0, 1.0, 1H), 8.23 (dd, J=8.8,1.0, 1H), 8.03 (d, J=1.6, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.32-7.27 (m,4H), 7.24 (dd, J=8.2, 1.6, 1H), 7.21-7.15 (m, 4H), 6.71 (d, J=8.3, 1H),6.22 (br d, J=8.8, 1H), 5.48 (t, J=8.5, 1H), 4.48 (d, J=8.3, 1H), 3.62(s, 3H).

B.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionicacid. A mixture of(S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino3-3,3-bis-(4-chloro-phenyl)-propionicacid methyl ester (49 mg, 0.064 mmol), THF (2 mL), and LiOH (1 M inwater, 1 mL) was stirred vigorously overnight at rt. The mixture wasacidified with conc. HCI (4 drops), diluted with THF to 3.5 mL, andpurified by preparative reverse phase HPLC to provide 37 mg (77%) of theacid as a white solid. HPLC: R_(T)=10.62 min. MS (ESI−): mass calcd. forC₂₈H₁₉Cl₂IN₄O₅S₂, 753.42; m/z found, 751/753 [M−H]⁻. ¹H NMR (500 MHz,MeOD): 8.32 (dd, J=7.1, 0.9, 1H), 8.24 (dd, J=8.8, 0.8, 1H), 7.95 (d,J=1.5, 1H), 7.76 (dd, J=8.8, 7.1, 1H), 7.38-7.21 (m, 9H), 6.72 (d,J=8.3, 1H), 5.37 (d, J=11.5, 1H), 4.50 (d, J=11.5, 1H).

Example 95

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyricacid

A.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyricacid methyl ester. The title compound (61 mg, 90%) was prepared from2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid (Example101, Part D) and (S)-2-amino-3-(4-chloro-phenyl)-3-methyl-butyric acidmethyl ester (Example 107, Part F) as in Example 94, Part A. ¹H NMR (500MHz, CDCl₃): 11.26 (s, 1H), 8.36 (dd, J=7.0, 1.0, 1H), 8.21 (dd, J=8.8,1.0, 1H), 8.07 (d, J=1.6, 1H), 7.72 (dd, J=8.8, 7.0, 1H), 7.35-7.25 (m,5H), 6.89 (d, J=8.3, 1H), 6.32 (br d, J=9.2, 1H), 4.97 (d, J=9.0, 1H),3.64 (s, 3H), 1.45 (s, 3H), 1.40 (s, 3H).

B.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyricacid. The title compound (22 mg, 37%) was prepared as in Example 94,Part B, along with 27 mg (44%) of the starting methyl ester. HPLC:R_(T)=10.30 min. MS (ESI−): mass calcd. for C₂₄H₂₀ClIN₄O₅S₂, 670.93; m/zfound, 669/671 [M−H]⁻. ¹H NMR (500 MHz, MeOD): 8.27(dd, J=7.1, 0.7, 1H),8.23(dd, J=8.8, 0.7, 1H), 7.96 (d, J=1.5, 1H), 7.75 (dd, J=8.8, 7.1,1H), 7.41-7.37 (m, 2H), 7.31 (dd, J=8.2, 1.6, 1H), 7.29-7.27 (m, 2H),6.89 (d, J=8.2, 1,H), 4.94 (s, 1H), 1.48 (s, 3H), 1.41 (s, 3H).

The compounds in Examples 96-98 may be prepared using methods analogousto those described in the preceding and subsequent examples.

Example 96

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-4-chloro-phenyl)-2-methyl-propionicacid

Example 97

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoylamino]-3-(3-bromo-phenyl)-propionicacid

Example 98

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoylamino]-3-(4-chloro-phenyl)-3-hydroxy-propionicacid

Example 99

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[(2S,1R)-2-(4-chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide

A.4-(S)-Benzyl-3-[(2R,3R)-3-(4-chloro-phenyl-3-hydroxy-2-methyl-propionyl]-oxazolidin-2-one.The title compound (1.32 g, 80%) was prepared from4-(S)-benzyl-3-propionyl-oxazolidin-2-one and 4-chlorobenzaldehyde as inExample 55, Part B. ¹H NMR (400 MHz, CDCl₃): 7.37-7.26 (m, 7H),7.23-7.17 (m, 2H), 5.12-5.08 (m, 1H), 4.69-4.62 (m, 1H), 422-4.13 (m,2H), 4.03 (dq, J=7.0, 3.6, 1H), 3.25 (dd, J=13.4, 3.3, 1H), 3.20 (d,J=2.5, 1H), 2.79 (dd, J=13.4, 9.4, 1H), 1.18 (d, J=7.0, 3H).

B. (2R,3R)-3-(4-Chloro-phenyl)-3-hydroxy-2-methyl-propionic acid. Thetitle compound (0.76 g, 100%) was prepared as in Example 55, Part C. ¹HNMR (400 MHz, CDCl₃): 7.36-7.32 (m, 2H), 7.32-7.28 (m, 2H), 5.16 (d,J=3.9, 1H), 2.81 (dq, J=7.2, 3.9, 1H), 1.15 (d, J=7.2, 3H).

C.(2R,3R)-3-(4-Chloro-phenyl)-3-tert-butyl-dimethyl-silanyloxy)-2-methyl-propionicacid. The title compound was prepared as in Example 55, Part D.Purification by flash chromatography (EtOAc/hexanes) provided 1.06 g(91%) of the desired silylated acid as a colorless oil. ¹H NMR (400 MHz,CDCl₃): 7.32-7.27 (m, 2H), 7.27-7.22 (m, 2H), 5.01 (d, J=5.3, 1H), 2.70(dq, J=7.2, 5.6, 1H), 1.11 (d, J=7.2, 3H), 0.88 (s, 9H), 0.03 (s, 3H),0.18 (s, 3H).

D.(1R,2S)-[2-[4-Chloro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-carbamicacid tert-butyl ester. The title compound (354 mg, 31%) was prepared asin Example 55, Part E. ¹H NMR (400 MHz, CDCl₃; rotameric broadening):7.28 (s, 4H), 4.90 (br s, 1H), 4.60 (br d, J=8.0, 1H), 3.77-3.65 (m,1H), 1.46 (s, 9H), 0.94 (s, 9H), 0.88 (d, J=6.8, 3H), 0.06 (s, 3H), 0.13(s, 3H).

E. (1S,2R)-2-Amino-1-(4-chloro-phenyl)-propan-1-ol hydrochloride salt.The title compound (195 mg, 100%) was prepared as in Example 55, Part F.MS (ESI+): mass calcd. for C₉H₁₂BrNO, 229.01; m/z found, 230, 232{M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.43-7.37 (m, 4H), 4.91 (d, J=3.4, 1H),3.50(dq, J=8, 3.5, 1H), 1.07 (d, J=6.8, 3H).

F.2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[(2S,1R)-2-(4-chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide.The title compound 442 mg, 67%) was obtained from2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid (Example101, Part D) and (1S,2R)-2-amino-1-(4-chloro-phenyl)-propan-1-olhydrochloride salt as in Example 1, Part C. HPLC: R_(T)=10.13 min. MS(ESI−): mass calcd. for C₂₂H₁₈ClIN₄O₄S₂, 628.89; m/z found, 627/629[M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.49 (s, 1H), 8.37 (dd, J=7.0, 0.8,1H), 8.23 (dd, J=8.8, 0.8, 1H), 8.07 (d, J=1.5, 1H), 7.73 (dd, J=8.8,7.1, 1H), 7.37-7.27 (m, 5H), 6.98 (d, J=8.3, 1H), 6.20 (d, J=8.1, 1H),4.95 (d, J=2.7, 1H), 4.42-4.38 (m, 1H), 2.65 (s, 1H), 1.03 (d, J=6.9,1H).

Example 100

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(3,4-dichloro-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide

The title compound may be prepared using methods described in thepreceding and subsequent examples.

Example 101

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[(2S,1R)-2-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide

A. 4-Iodo-2-nitrobenzoic acid. 4-Iodo-2-nitrotoluene (9.0 g, 34.2 mmol),KMnO₄(22.0 g, 139 mmol) and water (340 mL) were heated at reflux for 5h. The resulting brown suspension was filtered through a pad ofdiatomaceous earth, washing with water.

The basic filtrate was acidified with conc. HCl. The resulting solidswere collected by suction filtration and dried to afford 1.86 g of theacid. The mother liquor was extracted with DCM (3×), and the combinedextracts were dried (Na₂SO₄) and concentrated to afford an additional0.16 g of the benzoic acid. Total yield=2.02 g (20%). ¹H NMR (400 MHz,CD₃OD): 8.13 (d, J=1.6, 1H), 8.01 (dd, J=8.1, 1.6, 1H), 7.50 (d, J=8.1,1H).

B. Methyl 2-amino-4-iodobenzoate. The title compound (1.87 g, 91%) wasprepared as in Example 20, Part B. ¹H NMR (500 MHz, CDCl₃): 7.52 (d,J=8.5, 1H), 7.07 (d, J=1.6, 1H), 6.96 (dd, J=8.5, 1.6, 1H), 5.72 (br s,2H), 3.86 (s, 3H).

C. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acidmethyl ester. The title compound (1.87 g, 68%) was prepared as inExample 20, Part C (without DMAP). MS (ESI−): mass calcd. forC₁₄H₁₀IN₃O₄S₂, 474.92; m/z found, 474 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃):11.26 (br s, 1H), 8.40 (dd, J=7.0, 1.0, 1H), 824 (dd, J=8.8, 1.0, 1H),8.12 (d, J=1.5, 1H), 7.74 (dd, J=8.8, 7.0, 1H), 7.53 (d, J=8.5, 1H),7.32 (dd, J=8.5, 1.5, 1H), 3.91 (s, 3H).

D. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid. Thetitle compound (1.24 g, 69%) was prepared as in Example 20, Part D. ¹HNMR (500 MHz, CDCl₃): 11.03 (br s, 1H), 8.34 (dd, J=7.2, 1.1, 1H), 8.19(dd, J=8.8, 1.1, 1H), 8.09 (d, J=1.6, 1H), 7.69 (dd, J=8.8, 7.2, 1H),7.56 (d, J=8.5, 1H), 7.30 (dd, J=8.5, 1.6, 1H).

E.2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[(2S,1R)-2-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide.2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid wascoupled with (1S,2R)-2-amino-1-(3-bromo-phenyl)-propan-1-olhydrochloride salt (Example 108, Part E) as in Example 1, Part C (11 mg,16%). HPLC: R_(T)=10.19 min. MS (ESI−): mass calcd. for C₂₂H₁₈BrIN₄O₄S₂,673.34; m/z found, 671/673 [M−H]⁻. ^(H NMR ()500 MHz, CDCl₃): 11.45 (s,1H), 8.37 (d, J=7.0, 1H), 8.23 (d, J=8.8, 1H), 8.08(d, J=1.5, 1H), 7.73(dd, J=8.8, 7.1, 1H), 7.55-7.53 (m, 1H), 7.47-7.43(m, 1H), 7.334dd,J=8.2, 1.5, 1H), 7.31-7.21 (m, 3H), 6.99 (d, J=8.3, 1H), 6.19 (d, J=8.6,1H), 4.95-4.94 (m, 1H), 4.44-4.40 (m, 1H), 2.60 (s, 1H), 1.03 (d, J=6.9,3H).

The compounds in Examples 102-105 maybe prepared using methods analogousto those described in the preceding and subsequent examples.

Example 102

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionicacid

Example 103

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-phenyl)-butyricacid

Example 104

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-3-bromo-phenyl)-propyl]-4-iodo-benzamide

Example 105

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-acrylicacid

Example 106

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionicacid

A. 3,3-Bis-(4-chloro-phenyl)-propionic acid. To a suspension of4-chlorocinnamic acid (10.0 g, 54.8 mmol) in chlorobenzene (75 mL) at 0°C. was added AlCl₃ (12.0 g, 90 mmol) in 4 portions. The mixture wasstirred for 10 min at 0° C. then was warmed to 40° C. and stirred for 1h. Crushed ice (75 g) was added carefully, followed by water (75 mL).The aqueous layer was extracted with DCM (3×). The combined organicextracts were dried (Na₂SO₄) and concentrated to provide the crude acidas a tan solid. Recrystallization from EtOH provided 7.81 g (48%) of thedesired acid as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃): 7.31-7.22(m, 4H), 7.14-7.07 (m, 4H), 4.47 (t, J=8.0, 1H), 3.03 (d, J=7.9, 2H).

B.4-(S)-Benzyl-3-[3,3-bis-(4-chloro-phenyl)-propionyl]-oxazolidin-2-one. Asuspension of 3,3-bis-(4-chloro-phenyl)-propionic acid (3.0 g, 10.2mmol) in SOCl₂ (10 mL) was heated at reflux for 30 min. The mixture wascooled and concentrated, and the residue was azeotroped with toluene(3×) to give the acid chloride as a yellow liquid. ¹H NMR (400 MHz,CDCl₃): 7.32-7.26 (m, 4H), 7.15-7.10 (m, 4H), 4.55 (t, J=7.8, 1H), 3.57(d, J=7.8, 2H). To a stirred solution of 4-(S)-benzyl-oxazolidin-2-one(1.65 g, 9.3 mmol) in THF (46 mL) at −78 ° C. was added n-BuLi (1.6 M inhexanes, 6.1 mL, 9.8 mmol). After stirring 20 min at −78° C., a solutionof the acid chloride (10.2 mmol) in THF (7 mL) was added rapidly viacannula. The mixture was stirred overnight with slow warming to rt andwas quenched by addition of satd. aq. NH₄Cl. The mixture wasconcentrated, and the residue was diluted with water and extracted withDCM (3×). The combined organic extracts were dried (Na₂SO₄) andconcentrated. The residue was purified by flash chromatography(EtOAc/hexanes) to give 3.83 g (91%) of the title acyl imide as a whitesolid. ¹H NMR (400 MHz, CDCl₃): 7.33-7.25 (m, 7H), 7.25-7.19 (m, 4H),7.10-7.05 (m, 2H), 4.66 (t, J=7.7, 1H), 4.62-4.54 (m, 1H), 4.18-4.10 (m,2H), 3.76 (dd, J=17.0, 7.4, 1H), 3.65 (dd, J=17.0, 8.0, 1H), 3.10 (dd,J=13.5, 3.3, 1H), 2.64 (dd, J=13.4, 9.4, 1H).

C. 2,4,6-Triisoprorylbenzenesulfonyl azide. To a solution oftriisopropylbenzenesulfonyl chloride (6.94 g, 22.9 mmol) in acetone (115mL) at 0° C. was added a solution of NaN₃ (1.64 g, 25.2 mmol) in water(10 mL). The mixture was stirred for 30 min at 0° C. and then was warmedto rt and stirred for 1 h. The mixture was concentrated, diluted withwater, and extracted with DCM(3×). The combined organic extracts weredried (Na₂SO₄) and concentrated. The residue was purified by flashchromatography (EtOAc/hexanes) to provide 6.71 g (95%) of the desiredsulfonyl azide as a white solid. ¹H NMR (400 MHz, CDCl₃): 7.22 (s, 2H),4.05 (sept, J=6.7, 2H), 2.93 (sept, J=6.9, 1H), 1.29 (d, J=6.8, 12H),1.27 (d, J=6.9, 6H).

D.3-[2-(S)-Azido-3.3-bis-(4-chloro-phenyl)-propionyl]-4-(S)-benzyl-oxazolidin-2-one.A solution of4-(S)-benzyl-3-[3,3-bis-(4-chloro-phenyl)-propionyl]-oxazolidin-2-one(2.0 g, 4.4 mmol) in THF (25 mL) was cooled to −78° C. and added viacannula to a solution of potassium bis(trimethylsilyl)amide (0.5 M intoluene, 9.7 mL, 4.8 mmol) in THF (15 mL) at −78° C. After 30 min at−78° C., a solution of 2,4,6-triisopropylbenzenesulfonyl azide (1.77 g,5.7 mmol) in THF (15 mL) was cooled to −78° C. and added via cannula.After 1 min, the reaction was quenched by addition of AcOH (1.2 mL, 21mmol). The cooling bath was removed, and the mixture was allowed to warmto rt and stir overnight. The reaction mixture was diluted with waterand extracted with DCM (3×). The combined organic extracts were dried(Na₂SO₄) and concentrated. The residue was purified by flashchromatography (EtOAc/hexanes) to provide 1.58 g (72%) of the desiredazide as a white foam. ¹H NMR (400 MHz, CDCl₃): 7.38-7.15 (m, 13H), 5.94(d, J=11.0, 1H), 4.50 (d, J=11.0, 1H), 4.34-4.25 (m, 1H), 4.08 (dd,J=9.2, 2.4, 1H), 3.76 (dd, J=8.8, 8.1, 1H), 3.22 (dd, J=13.5, 3.3, 1H),2.77 (dd, J=13.5, 9.5, 1H).

E. (S)-2-Azido-3,3-bis-(4-chloro-phenyl)-propionic acid. To a solutionof3-[2-(S)-azido-3,3-bis-(4-chloro-phenyl)-propionyl]-4-(S)-benzyl-oxazolidin-2-one(1.53 g, 3.1 mmol) in 3:1 THF/water (60 mL) at 0° C. was added 30% aq.H₂O₂ (1.4 mL, 12.3 mmol) and LiOH.H₂O (259 mg, 6.2 mmol). The mixturewas stirred for 1 h at 0° C. Na₂SO₃ (2.52 g, 20 mmol) was added, and themixture was stirred for 30 min at 0° C., then warmed to rt, and stirredfor 1 h. The mixture was concentrated without external heating, and theresidue was diluted with water and extracted with DCM (3×). The aqueouslayer was acidified with conc. HCl and extracted with EtOAc (4×). Thecombined EtOAc extracts were dried (Na₂SO₄) and concentrated to providethe desired azido acid as a colorless solid (0.98 g, 94%). ¹H NMR (500MHz, CDCl₃): 7.33-7.24 (m, 6H), 7.21-7.18 (m, 2H), 4.52 (d, J=8.3, 1H),4.49 (d, J=8.3, 1H).

F. (S)-2-Amino-3,3-bis-(4-chloro-phenyl)-propionic acid.(S)-2-Azido-3,3-bis-(4-chloro-phenyl)-propionic acid (0.98 g, 2.9 mmol),Lindlar's catalyst (307 mg, 5 mol % Pd), and EtOAc (29 mL) was placed ina 500 mL Parr bottle. The bottle was pressurized with 50 psi of H₂ andshaken overnight in a Parr shaker apparatus. The mixture was dilutedwith MeOH, and the catalyst was removed by filtration throughdiatomaceous earth, rinsing with MeOH. The filtrate was concentrated toprovide 0.90 g (100%) of the desired amino acid as a white solid. MS(ESI−): mass calcd. for C₁₅H₁₃Cl₂NO₂, 309; m/z found, 308 [M−H]⁻.^(H NMR ()400 MHz, CD₃OD): 7.41-7.22 (m, 8H), 4.46 (d, J=9.1, 1H), 4.26(d, J=9.1, 1H).

G. (S)-2-tert-Butoxycarbonylamino-3,3-bis-(4-chloro-phenyl)-propionicacid methyl ester. To a solution of(S)-2-amino-3,3-bis-(4-chloro-phenyl)-propionic acid (0.90 g, 2.9 mmol)in MeOH (20 mL) at rt was added SOCl₂ (2 mL) carefully via pipette. Themixture was allowed to stand for 1 h at rt and was then concentrated. ¹HNMR indicated only partial conversion to the methyl ester. A mixture ofthe crude methyl ester, Boc₂O (0.77 g, 3.52 mmol), and 1 M NaOH (10 mL)was stirred rapidly for 2 h. The reaction mixture was extracted with DCM(3×), and the combined organic extracts were dried (Na₂SO₄) andconcentrated. The residue was purified by flash chromatography(EtOAc/hexanes) to provide 0.24 g (19%) of the desired N-Boc methylester. MS (ESI+): mass calcd. for C₂₁H₂₃Cl₂NO₄, 423.10; m/z found, 446[M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): 7.38-7.10 (m, 8H), 5.10-5,00 (br m,1H), 4.81 (br d, J=9.3, 1H), 4.34 (br d, J=8.4, 1H), 3.54 (s, 3H), 1.37(s, 9H).

H. (S)-2-Amino-3,3-bis-(4-chloro-phenyl)-propionic acid methyl ester. Toa solution of(S)-2-tert-butoxycarbonylamino-3,3-bis-(4-chloro-phenyl)-propionic acidmethyl ester (0.23 g, 0.54 mmol) in DCM (3 mL) at rt was added TFA (1mL). After 2 h, the mixture was concentrated, diluted with water, andextracted with DCM (3×). The combined organic extracts were dried(Na₂SO₄) and concentrated to provide 100 mg (57%) of the amine as a tanviscous oil. MS (ESI+): mass calcd. for C₁₆H₁₅Cl₂NO₂, 323.05; m/z found,324 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.32-7.19 (m, 8H), 4.26 (d, J=8.0,1H), 4.15 (app q, J=7.4, 1H), 3.57 (s, 3H), 1.46 (br d, J=6.6, 2H).

I.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionicacid methyl ester. The title compound (48 mg, 94%) was obtained from2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid and(S)-2-amino-3,3-bis-(4-chloro-phenyl)-propionic acid methyl ester as inExample 1, Part C. ¹H NMR (500 MHz, CDCl₃): 11.28 (s, 1H), 8.37 (dd,J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.72 (dd, J=8.8, 7.1, 1H),7.68 (d, J=1.9, 1H), 7.32-7.28 (m, 4H), 7.20-7.15 (m, 4H), 6.96 (d,J=8.5, 1H), 6.87 (dd, J=8.4, 2.0, 1H), 6.21 (br d, J=8.8, 1H), 5.50 (t,J=8.5, 1H), 4.48 (d, J=8.3, 1H), 3.63 (s, 3H).

J.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionicacid. The title compound (35 mg, 74%) was prepared as in Example 94,Part B. HPLC: R_(T)=10.54 min. MS (ESI−): mass-calcd. forC₂₈H₁₉Cl₃N₄O₅S₂, 661.96; m/z found, 659/661 [M−H]⁻. ^(1H NMR ()500 MHz,MeOD): 8.36-8.34 (m, 1H), 8.26-8.23 (m, 1H), 7.79-7.75 (m, 1H),7.62-7.61 (m, 1H), 7.39-7.26 (m, 8H), 7.00-6.98 (m, 1H), 6.88-6.86 (m,1H), 5.41-5.38 (m, 1H), 4.53-4.50 (m, 1H).

Example 107

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyricacid

A. 3-(4-Chloro-phenyl)-3-methyl-butyric acid. The title compound wasprepared from 3-methyl-2-butenoic acid as in Example 106, Part A.Recrystallization from EtOAc/hexanes provided 9.80 g (84%) of thedesired acid as a white solid. ¹H NMR (500 MHz, CDCl₃): 7.30-7.25 (m,4H), 2.63 (s, 2H), 1.43 (s, 6H).

B.(S)-4-Benzyl-3-[3-(4-chloro-phenyl)-3-methyl-butyryl]-oxazolidin-2-one.The title compound (3.72 g, 78%) was prepared as in Example 106, Part B.¹H NMR (400 MHz, CDCl₃): 7.38-7.22 (m, 7H), 7.15-7.09 (m, 2H), 4.52-4.45(m, 1H), 4.09-3.97 (m, 2H), 3.38 (d, J=16.0, 1H), 3,33 (d, J=16.0, 1H),3.12(dd, J=13.4, 3,3, 1H), 2.55 (dd, J=13.4, 9.8, 1H), 1.50 (s, 3H),1.49 (s, 3H).

C.3-[2-(S)-Azido-3-(4-chloro-phenyl)-3-methyl-butyryl]-4-(S)-benzyl-oxazolidin-2-one.The title compound (1.60 g, 72%) was prepared as in Example 106, Part D.¹H NMR (400 MHz, CDCl₃): 7.38-7.25 (m, 7H), 7.19-7.14 (m, 2H), 5.64 (s,1H), 4.27-4.19 (m, 1H), 4.03 (dd, J=9.0, 2.0, 1H), 3.66 (ddd, J=8.9,7.6, 0.6, 1H), 3.22 (dd, J=13.4, 3.2, 1H), 2.73 (dd, J=13.4, 9.6, 1H),1.55 (s, 3H), 1.53 (s, 3H).

D. (S)-2-Azido-3-(4-chloro-phenyl)-3-methyl-butyric acid. The titlecompound (0.89 g, 99%) was prepared as in Example 106, Part E. ¹H NMR(400 MHz, CDCl₃): 7.35-7.29 (m, 4H), 4.18 (s, 1H), 1.48 (s, 6H).

E. (S)-2-Azido-3-(4-chloro-phenyl)-3-methyl-butyric acid methyl ester. Amixture of (S)-2-azido-3-(4-chloro-phenyl)-3-methyl-butyric acid (0.89g, 3.5 mmol), powdered KHCO₃ (780 mg, 7.8 mmol), MeI (0.44 mL, 7.1mmol), and DMF (7 mL) was stirred rapidly at rt overnight. The mixturewas poured into water and extracted with Et₂O (3×). The combined organiclayers were washed with water (4×), dried (MgSO₄), and concentrated toprovide 0.90 g (96%) of the desired methyl ester as a colorless liquid.¹H NMR (400 MHz, CDCl₃): 7.34-7.28 (m, 4H), 4.10 (s, 1H), 3.64 (s, 3H),1.46 (s, 3H), 1.43 (s, 3H).

F. (S)-2-Amino-3-(4-chloro-phenyl)-3-methyl-butyric acid methyl ester.The title compound was prepared as in Example 106, Part F. The cruderesidue was purified by flash chromatography (EtOAc/hexanes) to give thestarting azide (0.39 g, 43%) and the desired amine as a colorless oil(0.39 g, 48%). MS (ESI+): mass calcd. for C₁₂H₁₆ClNO₂, 241.09; m/zfound, 242 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.29 (br s, 4H), 3.60 (s,3H), 3.59 (s, 1H), 1.38 (s, 3H), 1.37 (s, 3H).

G.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyricacid methyl ester. The title compound (57 mg, 97%) was obtained from2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid (37 mg,0.1 mmol) and (S)-2-amino-3-(4-chloro-phenyl)-3-methyl-butyric acidmethyl ester (0.048 g, 0.20 mmol) as in Example 1, Part C. ¹H NMR (500MHz, CDCl₃): 11.39 (s, 1H), 8.36 (dd, J=7.1, 1.0, 1H), 8.21 (dd, J=8.8,1.0, 1H), 7.72 (d, J=2.0, 1H), 7.71 (dd, J=8.8, 7.1, 1H), 7.34-7.26<m,4H), 7.14 (d, J=8.4, 1H), 6.94 (dd, J=8.4, 2.0, 1H), 6.32 (br d, J=9.0,1H), 4.99 (d, J=9.0, 1H), 3.64 (s, 3H), 1.46 (s, 3H), 1.41 (s, 3H).

H.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyricacid. The title compound (21 mg, 38%) was prepared as in Example 94,Part B. HPLC: R_(T)=10.19 min. MS (ESI−): mass calcd. forC₂₄H₂₀Cl₂N₄O₅S₂, 579.48; m/z found, 577/579{M−H]⁻. ¹H NMR (500 MHz,MeOD): 8.29 (dd, J=7.0, 0.9, 1H), 8.23 (dd, J=8.8, 0.9, 1H), 7.74 (dd,J=8.8, 7.1, 1H), 7.62 (d, J=2.0, 1H), 7.45-7.40 (m, 2H), 7.32-7.24 (m,2H), 7.15 (d, J=8.4, 1H), 6.95 (dd, J=8.4, 2.0, 1H), 4.96 (s, 1H), 1.49(s, 3H), 1.42 (s, 3H).

Example 108

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[(2S,1R)-2-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-4-chloro-benzamide

A.4-(S)-Benzyl-3-[(2R,3R)-3-(3-bromo-phenyl)-3-hydroxy-2-methyl-propionyl]-oxazolidin-2-one.The title compound (2.73 g, 76%) was prepared from4-(S)-benzyl-3-propionyl-oxazolidin-2-one and 3-bromobenzaldehyde as inExample 55, Part B. ¹H NMR (400 MHz, CDCl₃): 7.59-7.56 (m, 1H),7.42-7.38 (m, 1H), 7.37-7.28 (m, 4H), 7.25-7.18 (m, 3H), 5.11 (app t,J=2.8, 1H), 4.73-4.64 (m,1H), 4.22-4.16 (m, 2H), 4.02 (dq, J=7.0, 3.3,1H), 3.27 (d, J=2.6, 1H), 3.25 (dd, J=13.4, 3.4, 1H), 2.80 (dd, J=13.4,9.4, 1H), 1.18 (d, J=7.0, 3H).

B. (2R,3R)-3-(3-Bromo-phenyl)-3-hydroxy-2-methyl-propionic acid. Thetitle compound (1.54 g, 91%) was prepared as in Example 55, Part C. ¹HNMR (400 MHz, CDCl₃): 7.56-7.52 (m,1H), 7.45-7.39 (m,1H), 7.31-7.26(m,1H), 7.23 (dd, J=7.7, 7.7, 1H), 5.17 (d, J=3.6, 1H), 2.83 (dq, J=7.2,3.6, 1H), 1.15 (d, J=7.2, 3H).

C.(2R,3R)-3-(3-Bromo-phenyl)-3-(tert-butyl-dimethyl-silanyloxy)-2-methyl-propionicacid. The title compound (1.88 g, 85%) was prepared as in Example 55,Part D. MS (ESI−): mass calcd. for C₁₆H₂₅BrO₃Si, 372.08; m/z found, 371,373 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 7.48-7.45 (m, 1H), 7.42-7.37 (m,1H), 7.27-7.23 (m, 1H), 7.19 (dd, J=7.8, 7.8, 1H), 5.03 (d, J=5.0, 1H),2.73 (dq, J. =7.2, 4.8, 1H), 1.11 (d, J=7.2, 3H), 0.89 (s, 9H), 0.05 (s,3H), 0.16 (s, 3H).

D.(1R,2S)-[2-(3-Bromo-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-carbamicacid tert-butyl ester. The title compound (0.71 g, 32%) was prepared asin Example 55, Part E. MS (ESI+): mass calcd. for C₂₀H₃₄BrNO₃Si, 443.15;m/z found, 466, 468 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃; rotamericbroadening): 7.53-7.49 (m, 1H), 7.38-7.34 (m, 1H), 7.31-7.26 (m, 1H),7.18 (dd, J=7.8, 7.7, 1H), 4.90 (br s, 1H), 4.61 (br d, J=8.4, 1H),3.80-3.69 (m, 1H), 1.46is, 9H), 0.95 (s, 9H), 0.89 (d, J=6.0, 3H), 0.06(s, 3H), 0.11 (s, 3H).

E. (1S,2R)-2-Amino-1-(3-bromo-phenyl)-propan-1-ol hydrochloride salt. Toa solution of(1R,2S)-[2-(3-bromo-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-carbamicacid tert-butyl ester (0.71 g, 1.6 mmol) in MeOH (10 mL) was added 4 MHCl in dioxane (3 mL). After 1 h, the mixture was diluted with basicbrine (prepared by dissolving a quantity of NaOH in brine), andextracted with DCM (4×). The combined organic layers were dried (Na₂SO₄)and concentrated. The residue was purified by preparative reverse phaseHPLC. The TFA salt thus obtained was diluted with basic brine andextracted with DCM (4×). The combined organic layers were dried (Na₂SO₄)and concentrated. The residue was diluted with MeOH and treated with 4 MHCl in dioxane. The mixture was concentrated to provide the desired HClsalt. MS (ESI+): mass calcd. for C₉H₁₂BrNO, 229.01; m/z found, 230, 232[M+H]⁺. ¹H NMR (400 MHz, CDCl₃; free base): 7.53-7.50 (m, 1H), 7.43-7.38(m, 1H), 7.27-7.24 (m, 1H), 7.21 (dd, J=7.7, 7.6, 1H), 4.53 (d, J=4.0,1H), 3.30-3.18 (m, 1H), 0.93 (d, J=6.5, 3H).

F.2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[(2S,1R)-2-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-4-chloro-benzamide.The title compound (7 mg, 12%) was obtained from2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid and(1S,2R)-2-amino-1-(3-bromo-phenyl)-propan-1-ol hydrochloride salt as inExample 1, Part C. HPLC: R_(T)=10.08 min. MS (ESI−): mass calcd. forC₂₂H₁₈BrClN₄O₄S₂, 581.89; m/z found, 579/581 [M−H]⁻. ¹H NMR (500 MHz,CDCl₃): 11.58 (s, 1H), 8.38 (dd, J=7.0, 0.9, 1H), 8.22 (dd, J=8.8, 0.9,1H), 7.74-7.71 (m, 2H), 7.55-7.53 (m, 1H), 7.47-7.43 (m, 1H), 7.31-7.22(m, 2H), 6.95 (dd, J=8.4, 2.0, 1H), 6.19 (d, J=8.5, 1H), 4.95 (d, J=2.7,1H), 4.48-4.39 (m, 1H), 2.61 (s, 1H), 1.04 (d, J=6.9, 3H).

The compounds in Examples 109-114 may be prepared using methodsanalogous to those described in the preceding and subsequent examples.

Example 109

2-[2-(Benzooxazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionicacid

Example 110

2-[2-(Benzooxazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid

Example 111

2-[2-(Benzo[1,3]dioxole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid

Example 112

2(Benzo[1,3]dioxole-4-sulfonylamino)-4-chloro-N-[2-(4-chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-benzamide

Example 113

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester

Example 114

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid pyridin-3-ylmethyl ester

Example 115

(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-phenyl)-propionicacid

(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino]-4-iodo-benzoylamino]-3-(3-bromo-phenyl)-propionicacid was prepared as in EXAMPLE 4, substituting (1S,2S)-pseudoephedrineglycinamide hydrate in Part A. HPLC: R_(T)=9.93 min. MS (ESI−): masscalcd. for C₂₂H₁₆BrIN₄O₅S₂, 687.33; m/z found, 685/687 [M−H]⁻. ¹H NMR(400 MHz, CDCl₃): 11.23 (s, 1H), 8.33 (dd, J=7.1, 0.8, 1H), 8.15 (dd,J=8.8, 0.8, 1H), 8.01 (d, J=1.5, 1H), 7.70 (dd, J=8.8, 7.1, 1H),7.37-7.35 (m, 1H), 7.30 (s, 1H), 7.23 (dd, J=8.3, 1.5, 1H), 7.16-7.06(m, 2H), 6.92 (d, J=8.3, 1H), 6.66 (d, J=7.4, 1H), 4.99 (q, J=6.1, 1H),3.36-3.17 (m, 2H).

Example 116

(2S,3R)-3-(3,4-Dichloro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-butyricacid methyl ester

2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-benzoic acid was coupled to(2S,3R)-2-amino-3-(3,4-dichloro-phenyl)-butyric acid methyl ester as inExample 1, Part C, to afford the title compound. HPLC: R_(T)=12.39 min.MS (ESI+): mass calcd. for C₂₄H₁₉Cl₂F₂IN₂O₅S, 683.29; m/z found, 683/685[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 11.29 (s, 1H), 8.11 (d, J=1.6, 1H),7.52-7.47 (m, 1H), 7.42 (dd, J=8.3, 1.6, 1H), 7.37 (d, J=13.9, 1H), 7.24(d, J=2.1, 2H), 7.11 (d, J=8.3, 1H), 7.02-6.98 (m, 3H), 6.65 (d, J=8.3,1H), 4.95-4.91 (m, 1H), 3.26 (s, 3H), 3,31 (quin, J=7.2, 1H), 1.43 (d,J=7.2, 3H).

Example 117

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid wascoupled to (S)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methylester hydrochloride as in EXAMPLE 1, Part C. The resulting methyl esterwas hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound.HPLC: R_(T)=10.98 min. MS (ESI−): mass calcd. for C₂₂H₁₅Cl₃N₄O₅S₂,585.87; m/z found, 583/585 [M−H]⁻. ^(H NMR ()500 MHz, CDCl₃): 11.35(s,1H), 8.36 (dd, J=7.0, 0.8, 1H), 8.21 (dd, J=8.8, 0.8, 1H), 7.74-7.69(m, 1H), 7.34 (d, J=8.2, 1H), 7.21 (d, J=2.0, 1H), 7.15 (d, J=8.4, 1H),6.97 (dd, J=8.2, 2.0, 1H), 6.93 (dd, J=8.4, 2.0, 1H), 6.44 (d, J=7.0,1H), 4.95-5.00 (m, 1H), 3.32-3.16 (m, 2H).

Example 118

(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acidwas-coupled to (R)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methylester hydrochloride as in EXAMPLE 1, Part C. The resulting methyl esterwas hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound.HPLC: R_(T)=10.97 min. MS (ESI−): mass-calcd. for C₂₂H₁₅Cl₃N₄O₅S₂,585.87; m/z found, 583/585 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.36 (s,1H), 8.36 (dd, J=7.0, 0.8, 1H), 8.21 (dd, J=8.8, 0.6, 1H), 7.74-7.70 (m,2H), 7.34 (d, J=8.2, 1H), 7.21 (d, J 1.9, 1H), 7.15 (d, J=8.4, 1H), 6.97(dd, J=8.2, 2.0, 1H), 6.93 (dd, J=8.4, 2.0, 1H), 6.44 (d, J=7.0, 1H),4.98 (q, J=5.7, 1H), 3.32-3.15 (m, 2H).

Example 119

(S)-2-[4-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid

2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-benzoic acid was coupled to(S)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl esterhydrochloride as in EXAMPLE 1, Part C. The resulting methyl ester washydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC:R_(T)=11.00 min. MS (ESI−): mass calcd. for C₂₂H₁₅Cl₃F₂N₂O₅S₂, 563.79;m/z found, 561/563 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.45 (s, 1H), 7.75(d, 1.9, 1H), 7.56-7.45 (m, 1H), 7.36 (d, J=8.2, 1H), 7.29-7.25 (m, 2H),7.05-6.97 (m, 4H), 6.62 (d, J=7.0, 1H), 5.03 (q, J=5.5, 1H), 3.39-3.17(m, 2H).

Example 120

(R)-2-[4-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid

2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-benzoic acid was coupled to(R)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl esterhydrochloride as in EXAMPLE 1, Part C. The resulting methyl ester washydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC:R_(T)=11.00 min. MS (ESI−): mass calcd. for C₂₂H₁₅Cl₃F₂N₂O₅S, 563.79;m/z found, 561/563 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.45 (s, 1H), 7.75(d, J=1.9, 1H), 7.53-7.44 (m, 1H), 7.36 (d, J=8.2, 1H), 7.31-7.25 (m,2H), 7.06-6.96 (m, 4H), 6.61 (d, J=6.9, 1H), 5.03 (d, J=5.6, 1H),3.38-3.17 (m, 2H).

Example 121

anti-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionicacid

A solution of2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-oxo-propionicacid methyl ester (35 mg, 0.057 mmol) in THF (2 mL) was cooled to −78°C. and lithium tri-sec-butylborohydride (L-Selectride; 1 M in THF, 86μL, 0.086 mmol) was added. The mixture was stirred at −78° C. for 1 hand water (0.1 mL), EtOH (0.1 mL), 15% NaOH (0.1 mL), and 30% H₂O₂ (0.1mL) were added and the solution was warmed to rt. The mixture wasdiluted with satd. aq. Na₂S₂O₃ and water and extracted with EtOAc (3×).The combined organic layers were washed with brine, dried (MgSO₄), andconcentrated. The crude product was purified by reverse phase HPLC toprovide2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionicacid methyl ester as a single diastereomer (20 mg, 57%). The methylester was hydrolyzed as in Example 2, Part E, to provide the titlecompound (73%). HPLC: R_(T)=9.51 min. MS (ESI−): mass calcd. forC₂₂H₁₅Cl₃N₄O₅S₂, 601.87; m/z found, 599/601 [M−H]⁻. ¹H NMR (400 MHz,CDCl₃): 11.31 (s, 1H), 8.34 (dd, J=7.0, 0.6, 1H), 8.19 (dd, J=8.8, 0.6,1H), 7.71 (dd, J=8.8, 7.1, 1H), 7.64 (d, J=1.9, 1H), 7.43 (d, J=1.7,1H),7.36 (d, J=8.3, 1H), 7.23 (d, J=8.5, 1H), 7.18 (dd, J=8.3, 1.8, 1H),7.01 (d, J=7.3, 1H), 6.86 (dd, J=8.4, 1.9, 1H), 5.37 (d, J=3.7, 1H),5.10 (dd, J=7.3, 3.9, 1H).

Example 122

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionic-acidmethyl ester

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid wascoupled to (S)-2-amino-3-(3-bromo-4-chloro-phenyl)-propionic acid methylester hydrochloride as in EXAMPLE 1, Part C, to afford the titlecompound. HPLC: R_(T)=10.85 min. MS (ESI+): mass calcd. forC₂₃H₁₇BrClIN₄O₅S₂, 735.80; m/z found, 735/737 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 11.31 (s, 1H), 8.36 (d, J=7.1, 1H), 8.22 (d, J=8.7, 1H), 8.08(d, J=1.4, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.36-7.28 (m, 3H), 6.96-6.90(m, 2H), 6.46 (d, J=7.1, 1H), 4.93 (q, J=5.5, 1H), 3.82(s, 3H),3.23-3.10 (m, 2H).

Example 123

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid methyl ester

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid wascoupled to (S)-2-amino-3-(3-bromo-4-fluoro-phenyl)-propionic acid methylester hydrochloride as in EXAMPLE 1, Part C, to afford the titlecompound. HPLC: R_(T)=10.57 min. MS (ESI+): mass calcd. forC₂₃H₁₇BrFIN₄O₅S₂, 719.34; m/z found, 719/721 {M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 11.31 (s, 1H), 8.36 (dd, J=7.0, 0.7, 1H), 8.22 (dd, J=8.8, 0.7,1H), 8.08 (d, J=1.5, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.32 (dd, J=8.2,1.5, 1H), 7.23 (dd, J=6.5, 2.1, 1H), 7.06-6.99 (m, 1H), 6.98-6.89 (m,2H), 6.46 (d, J=6.9, 1H), 4.93 (q, J=5.5, 1H), 3.82 (s, 3H), 3.25-3.08(m, 2H).

Example 124

(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester

4-Iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid was coupled to(S)-2-amino-3-(3-bromo-4-fluoro-phenyl)-propionic acid methyl esterhydrochloride as in EXAMPLE 1, Part C, to afford the title compound.HPLC: R_(T)=10.30 min. MS (ESI+): mass calcd. for C₂₅H₁₉BrFIN₄O₅S,713.32; m/z found, 713/715 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 11.09 (s,1H), 8.99 (d, J=1.7, 1H), 8.92 (d, J=1.7, 1H), 8.58 (dd, J=7.3, 1.3,1H), 8.33 (dd, J=8.5, 1.3, 1H), 8.09 (d, J=1.5, 1H), 7.90 (dd, J=8.3,7.5, 1H), 7.30 (dd, J=8.2, 1.5, 1H), 7.25-7.23 (m,1H), 7.05-6.98 (m,1H),6.98-6.90 (m, 2H), 6.43 (d, J=7.1, 1H), 4.90 (q, J=5.5, 1H), 3.81 (s,3H), 3;20-3.08 (m, 2H).

Example 125

(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-propionicacid methyl ester

2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-benzoic acid was coupled to(S)-2-amino-3-(3-bromo-4-fluoro-phenyl)-propionic acid methyl esterhydrochloride as in EXAMPLE 1, Part C, to afford the title compound.HPLC: R_(T)=10.54 min. MS (ESI+): mass calcd. for C₂₃H₁₇BrF₃IN₂O₅S,697.26; m/z found, 697/699 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 11.37 (s,1H), 8.11 (d, J=1.4, 1H), 7.55-7.44 (m, 1H), 7.40 (dd, J=8.3, 1.4, 1H),7.27-7.26 (m, 1H), 7.09-7.04 (m, 2H), 7.02-6.96 (m, 3H), 6.63 (d, J=6.8,1H), 4.98 (q, J=5.6, 1H), 3.81 (s, 3H), 3.27-3.13 (m, 2H).

Example 126

(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid

(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford thetitle compound. HPLC: R_(T)=9.68 min. MS (ESI−): mass calcd. forC₂₄H₁₇BrFIN₄O₅S, 699.29; m/z found, 697/699 [M−H]⁻. ¹H NMR (500 MHz,CDCl₃): 10.86 (s, 1H), 9.00 (d, J=1.7, 1H), 8.91 (d, J=1.7, 1H), 8.53(dd, J=7.4, 1.2, 1H), 8.31 (dd, J=8.5, 1.1, 1H), 8.08 (d, J=1.4, 1H),7.88 (dd, J=8.3, 7.6, 1H), 7.33 (dd, J=6.3, 1.8, 1H), 7.28 (dd, J=8.3,1.5, 1H), 7.08-6.98 (m, 2H), 6.86 (d, J=8.2, 1H), 6.35 (d, J=7.5,1H),4.89 (d, J=5.9, 1H), 3.30-3.07 (m, 2H).

Example 127

(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-propionicacid

(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-propionicacid methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford thetitle compound. HPLC: R_(T)=9.93 min. MS (ESI−): mass calcd. forC₂₂H₁₅BrF₃IN₂O₅S, 683.23; m/z found, 681/683 [M−H]⁻. ¹H NMR (500 MHz,CDCl₃): 11.27 (s, 1H), 8.07 (,d, J=1.4, 1H), 7.54-7.44 (m, 1H), 7.38(dd, J=8.3, 1.4, 1H), 7.35 (dd, J=6.4, 1.9, 1H), 6.96-7.13 (m, 5H), 6.63(d, J=6.9, 1H), 5.00 (q, J=5.7, 1H), 3.39-3.14 (m, 2H).

Example 128

(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[1-(3-chloro-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethyl]-benzamide

A.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid methyl ester. To a solution of2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid (300mg, 0.81 mmol) in 1:4 THF/DMF (5 mL) at rt was added pyridine (0.196 mL,2.4 mmol) followed by HATU (616 mg, 1.6 mmol). The mixture was stirredfor 1 h, and (S)-3,4-dichlorophenylalanine methyl ester hydrochloride(461 mg, 1.6 mmol) and Hünig's base (0.282 mL, 1.6 mmol) were added.After 18 h, the mixture was poured into 1 N HCl and extracted with EtOAc(4×). The combined organic extracts were washed with water (3×), dried(Na₂SO₄), and concentrated to provide the crude methyl ester, which wasused without further purification. ¹H NMR (400 MHz, CDCl₃): 11.48 (br s,1H), 8.38 (dd, J=7.0, 1.0, 1H), 8.23 (dd, J=8.8, 1.0, 1H), 7.73 (dd,J=8.8, 7.1, 1H), 7.73 (d, J=1.8, 1H), 7.34 (d, J=8.2, 1H), 7.19 (d,J=8.4, 1H), 7.14 (d, J=2.0, 1H), 6.96 (dd, J=8.4, 2.0, 1H), 6.90 (dd,J=8.2, 2.0, 1H), 6.48 (br d, J=7.1, 1H), 5.00-4.93 (m, 1H), 3.82 (s,3H), 3.22 (dd, J=14.1, 5.9, 1H), 3.16 (dd, J=14.0, 5.1, 1H).

B.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid. A mixture of(S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid methyl ester (0.81 mmol), THF (10 mL), and LiOH (2 M in water, 5mL) was stirred vigorously overnight at rt. The mixture was poured intowater, acidified to pH 1 with-conc. HCl, and extracted with EtOAc (4×).The combined organic layers were dried (Na₂SO₄) and concentrated toprovide the desired acid as a tan solid. The acid was purified bypreparative reverse phase HPLC to provide 0.44 g (94%, 2 steps) of theacid as a white solid. HPLC: R_(T)=10.08 min. MS (ESI−): mass calcd. forC₂₂H₁₅Cl₃N₄S₅O₂, 583.95; m/z found, 583 [M−H]⁻. ¹H NMR (400 MHz, CD₃OD):8.34 (dd, J=7.0, 1.0, 1H), 8.25 (dd, J=8.8, 1.0, 1H), 7.77 (dd, J=8.8,7.0, 1H), 7.66 (d, J=2.0, 1H), 7.45-7.37 (m, 3H), 7.18 (dd, J=8.2, 2.0,1H), 6.99 (dd, J=8.5, 2.1, 1H), 4.75 (dd, J=9.3, 5.2, 1H), 3.28 (dd,J=14.0, 5.1, 1H), 3.03 (dd, J=14.0, 9.4, 1H).

C.(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[1-(3-chloro-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethyl]-benzamide.The title compound (29 mg, 48%) was obtained from(S)-2-[2-benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid and 3-chlorobenzylamine as in Example 1, Part C. HPLC: R_(T)=10.95min. MS (ESI−): mass calcd. for C₂₉H₂₁Cl₄N₅O₄S₂, 709.45; m/z found,706/708 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.55 (s, 1H), 8.39 (dd, J=7.0,0.9, 1H), 8.22 (dd, J=8.8, 0.8, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.70 (d,J.=2.0, 1H), 7.38-7.30 (m, 3H), 7.16 (d, J=0.5, 1H), 7.05-6.99 (m, 2H),6.96 (dd, J=8.5, 2.0, 1H), 6.88-6.81 (m, 1H), 5.87-5.80 (m, 1H),4.70-4.61 (m, 1H), 4.49-4.41 (m, 1H), 4.34-4.26 (m, 1H), 3.17-3.09 (m,1H), 3.06-2.96 (m, 1H).

Example 129

(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[1-benzylcarbamoyl-2-(3,4-dichloro-phenyl)-ethyl]-4-chloro-benzamide

The title compound (19 mg, 33%) was obtained from(S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid and benzyl amine as in Example 1, Part C. HPLC: R_(T)=10.73 min. MS(ESI−): mass calcd. for C₂₉H₂₂Cl₃N₅O₄S₂, 675.01; m/z found, 672/674[M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.59 (s, 1H), 8.38 (dd, J=7.1, 0.7,1H), 8.20 (d, J=8.8, 1H), 7.74-7.71 (m, 2H), 7.37-7.25 (m, 5H),7.13-7.11 (m, 2H), 7.03-6.98 (m, 1H), 6.96-6.87 (m, 2H), 5.79-5.71 (m,1H), 4.66-4.61 (m,1H), 4.50-4.45 (m, 1H), 4.33-4.29 (m, 1H), 3.14-3.10(m, 1H), 3.00-2.96 (m,1H),

Example 130

(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(3,4-dichloro-phenyl)-1-(4-fluoro-benzylcarbamoyl)-ethyl]-benzamide

The title compound (27 mg, 46%) was obtained from(S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid and 4-fluorobenzyl amine as in Example 1, Part C. HPLC: R_(T)=10.66min. MS (ESI−): mass calcd. for C₂₉H₂₁Cl₃FN₅O₄S₂, 693.00; m/z found,690/692 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.55 (s,1H), 8.38 (dd, J=7.0,0.8, 1H), 8.21 (dd, J=8.8, 0.6, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.68 (d,J=1.9, 1H), 7.35-7.32 (m, 1H), 7.30-7.25 (m, 2H), 7.12-7.07 (m, 2H),7.05-6.99 (m, 5H), 6.94 (dd, J=8.4, 1.9, 1H), 6.88-6.81 (m, 1H),5.79-5.72 (m, 1H), 4.67-4.59 (m, 1H), 4.47-4.40 (m,1H), 4.29-4.25 (m,1H), 3.15-3.11 (m,1H), 3.00-2.96 (m,1H).

Example 131

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid

A. 4-Bromo-2-nitrobenzoic acid. The title compound (1.22 g, 22%) wasprepared as in Example 20, Part A. MS (ESI−): mass calcd. for C₇H₄BrNO₄,244.93; m/z found, 244 [M−H]⁻. ¹H NMR (400 MHz, CD₃OD): 8.07 (d, J=1.9,1H), 7.85 (dd, J=8.2, 1.9, 1H), 7.65 (d, J=8.2, 1H).

B. Methyl 2-amino-4-bromobenzoate. The title compound (2.89 g, 93%) wasprepared as in Example 20, Part B. ¹H NMR (400 MHz, CDCl₃): 7.70 (d,J=8.6, 1H), 6.84 (d, J=1.9, 1H), 6.75 (dd, J=8.6, 1.9, 1H), 5.78 (br s,2H), 3.86 (s, 3H).

C. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoic acidmethyl ester. The title compound (3.95 g, 75%) was prepared as inExample 20, Part C (without DMAP). MS (ESI−): mass calcd. forC₁₄H₁₀BrN₃O₄S₂, 429.93; m/z found, 426 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃):11.34 (br s, 1H), 8.40 (dd, J=7.0, 0.9, 1H), 8.24 (dd, J=8.8, 0.9, 1H),7.92 (d, J=1.8, 1H), 7.74 (dd, J=8.8, 7.0, 1H), 7.72 (d, J=8.5, 1H),7.10 (dd, J=8.5, 1.8, 1H), 3.92 (s, 3H).

D. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromobenzoic acid. Thetitle compound (2.76 g, 97%) was prepared as in Example 20, Part D. ¹HNMR (500 MHz, CDCl₃): 11.14 (br s, 1H), 8.42 (dd, J=7.2, 1.1, 1H), 8.26(dd, J=8.8, 1.1, 1H), 7.98 (d, J=1.6, 1H), 7.82 (d, J=8.5, 1H), 7.75(dd, J=8.8,7.2, 1H), 7.16 (dd, J=8.5, 1.6, 1H).

E.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid methyl ester. The title compound (61 mg, 95%) was prepared from2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromobenzoic acid and(S)-3,4-dichlorophenylalanine methyl ester hydrochloride as in Example1, Part C. ¹H NMR (400 MHz, CDCl₃): 11.43 (br s, 1H), 8.38 (dd, J=7.0,1.0, 1H), 8.23 (dd, J=8.8, 1.0, 1H), 7.90 (t, J=1.0, 1H), 7.73 (dd,J=8.8, 7.0, 1H), 7.35 (d, J=8.2, 1H), 7.14 (d, J=2.0, 1H), 7.11 (d,J=1.0, 2H), 6.89 (dd, J=8.2, 2.1, 1H), 6.48 (br d, J=7.1, 1H), 5.00-4.92(m, 1H), 3.82 (s, 3H), 3.22 (dd, J=14.0, 5.8, 1H), 3.16 (dd, J=14.0,5.1, 1H).

F.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid. The title compound (43 mg, 72%) was prepared as in Example 94,Part B. HPLC: R_(T)=10.14 min. MS (ESI−): mass calcd. for C_(22l H)₁₅BrCl₂N₄O₅S₂, 630.32; m/z found, 627/629 [M−H]⁻. ¹H NMR (500 MHz,MeOD): 8.32 (dd, J=7.0, 0.8, 1H), 8.24 (dd, J=8.8, 0.9, 1H), 7.81 (d,J=1.8, 1H), 7.76 (dd, J=8.8, 7.1, 1H), 7.44-7.38 (m, 2H), 7.31 (d,J=8.4, 1H), 7.19-7.13 (m, 2H), 4.76-4.70 (m, 1H), 3.29-3.24 (m, 1H),3.02 (dd, J=14.0, 9.4, 1H).

Example 132

(S)-3-(3,4-Dichloro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid

4-Iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid was coupled with(S)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl esterhydrochloride as in Example 1, Part C. The resulting methyl ester washydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC:R_(T)=10.05 min. MS (ESI−): mass calcd. for C₂₄H₁₇Cl₂IN₄O₅S, 671.29; m/zfound, 669/671 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 10.86 (s, 1H), 9.01 (d,J=1.6, 1H), 8.92 (d, J=1.6, 1H), 8.55 (dd, J=7.3,1.0, 1H), 8.32 (dd,J=8.5, 1.0, 1H), 8.08 (d, J=1.3, 1H), 7.91-7.88 (m, 1H), 7.34 (d, J=8.2,1H), 7.30-7.24 (m, 2H), 6.98 (dd, J=8.2, 1.9, 1H), 6.88 (d, J=8.2, 1H),6.38 (d, J=7.3, 1H), 4.90 (q, J=5.9, 1H), 3.28-3.12 (m, 2H).

Example 133

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(2,4-dichloro-phenyl)-propionicacid

(S)-2-tert-Butoxycarbonylamino-3-(2,4-dichloro-phenyl)-propionic acidwas treated as in EXAMPLE 2, Part A, to produce(S)-2-amino-3-(2,4-dichloro-phenyl)-propionic acid methyl esterhydrochloride as a white solid. This ester was coupled to2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid as inEXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as inEXAMPLE 2, Part E, to afford the title compound. HPLC: R_(T)=10.19 min.MS (ESI−): mass calcd. for C₂₂H₁₅Cl₂IN₄O₅S₂, 677.32; m/z found, 675/677[M−H]⁻. ^(H NMR ()500 MHz, CDCl₃): 11.16 (s, 1H), 8.34 (d, J=7.1, 1H),8.21 (d, J=8.8, 1H), 8.07-8.05 (m, 1H), 7.71 (dd, J=8.8, 7.1, 1H),7.40-7.39 (m, 1H), 7.32-7.26 (m, 1H), 7.24-7.22 (m, 2H), 6.94 (d, J=8.3,1H), 6.53 (d, J=7.5, 1H), 5.02-4.95 (m, 1H), 3.53-3.44 (m, 1H),3.34-3.24 (m, 1H).

Example 134

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(2,4-dichloro-5-fluoro-phenyl)-propionicacid

The title compound was prepared as in Example 4, substituting2,4-dichloro-5-fluorobenzyl bromide in Part B. HPLC: R_(T)=10.21 min. MS(ESI−): mass calcd. for C₂₂H₁₄Cl₂FIN₄O₅S₂, 695.31; m/z found, 693/695[M−H]⁻. ¹H NMR (400 MHz, DMSO-d₆): 11.75 (s, 1H), 9.07 (d, J=7.9, 1H),8.42-8.40 (m, 2H), 7.88 (t, J=7.9, 1H), 7.83-7.81 (m, 2H), 7.46-7.44 (m,2H), 7.38-7.36 (m, 1H), 4.68-4.65 (m, 1H), 3.40-3.20 (m, 1H), 3.14-3.08(m, 1H).

Example 135

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-iodo-phenyl)-propionicacid

The title compound was prepared as in EXAMPLE 4, substituting3-iodobenzyl bromide in Part B. HPLC: R_(T)=10.03 min. MS (ESI−): masscalcd. for C₂₂H₁₆I₂N₄O₅S₂, 734.33; m/z found, 733 [M−H]⁻. ¹H NMR (400MHz, DMSO-d₆): 11.76 (s,1H), 9.01 (d, J=7.9, 1H), 8.42-8.40 (m, 2H),7.88 (t, J=7.9, 1H), 7.82 (d, J=1.5, 1H), 7.68 (s, 1H), 7.57 (d, J=7.9,1H), 7.43 (d, J=8.2, 1H), 7.36 (d, J=8.3, 1H), 7.29 (d, J=7.6, 1H), 7.08(t, J=7.7, 1H), 4.59-4.54 (m, 1H), 3.18-3.13 (m, 1H), 2.99-2.93 (m, 1H).

Example 136

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-3-iodo-phenyl)-propionicacid methyl ester

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid wascoupled to (S)-2-amino-3-(4-chloro-3-iodo-phenyl)-propionic acid methylester hydrochloride as in EXAMPLE 1, Part C, to afford title compound.HPLC: R_(T)=10.87 min. MS (ESI+): mass calcd. for C₂₃H₁₇ClI₂N₄O₅S₂,782.80; m/z found, 783/785 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 11.31(s,1H), 8.37 (dd, J=7.0, 0.9, 1H), 8.23 (dd, J=8.8, 0.9, 1H), 8.09 (d,J=1.5, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.55 (d, J=2.0, 1H), 7.35-7.33(m, 2H), 7.00-6.94 (m, 2H), 6.46 (d, J=7.1, 1H), 4.97-4.91 (m, 1H), 3.82(s, 3H), 3.21-3.10 (m, 2H).

Example 137

(S)-3-(4-Chloro-3-iodo-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester

4-Iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid was coupled to(S)-2-amino-3-(4-chloro-3-iodo-phenyl)-propionic acid methyl esterhydrochloride as in EXAMPLE 1, Part C, to afford title compound. HPLC:R_(T)=10.61 min. MS (ESI+): mass calcd. for C₂₅H₁₉ClI₂N₄O₅S, 776.77; m/zfound, 777/779 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 11.09 (s, 1H), 9.01-8.98(m, 1H), 8.95-8.92 (m, 1H), 8.58 (d, J=7.3, 1H), 8.34 (d, J=8.5, 1H),8.11 (d, J=1.5, 1H), 7.94-7.88 (m, 1H), 7.57 (d, J=1.9, 1H), 7.36-7.26(m, 2H), 7.00-6.94 (m, 2H), 6.42 (d, J=6.3, 1H), 4.95-4.88 (m, 1H), 3.81(s, 3H), 3.20-3.07 (m, 2H).

Example 138

(S)-3-(4-Chloro-3-iodo-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid

(S)-3-(4-Chloro-3-iodo-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester was hydrolyzed as in Example 2, Part E, to afford thetitle compound. HPLC: R_(T)=10.01 min. MS (ESI−).: mass calcd. forC₂₄H₁₇ClI₂N₄O₅S₂, 762.74; m/z found, 761/763 [M−H]⁻. ¹H NMR (500 MHz,CDCl₃): 10.92 (s, 1H), 8.99 (d, J=1.7, 1H), 8.92 (d, J=1.6, 1H),8.56-8.52 (m, 1H), 8.33-8.29 (m, 1H), 8.10 (d, J=1.3, 1H), 7.88 (m, 1H),7.62 (d, J=1.8, 1H), 7.35-7.25 (m, 2H), 7.08-7.02 (m, 1H), 6.89 (d,J=8.2, 1H), 6.31 (d, J=7.3, 1H), 4.92-4.86 (m, 1H), 3.24-3.08 (m, 2H).

Example 139

(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(3,4-dichloro-phenyl)-1-phenylcarbamoyl-ethyl]-benzamide

The title compound (25 mg, 45%) was prepared from(S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid and aniline as in Example 1, Part C. HPLC: R_(T)=10.81 min. MS(ESI−): mass calcd. for C₂₈H₂₀Cl₃N₅O₄S₂, 660.98; m/z found, 658/660[M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.54 (s, 1H), 8.39 (dd, J=7.1, 1.0,1H), 8.19 (dd, J=8.8, 0.8, 1H), 7.75-7.67 (m, 2H), 7.67-7.62 (m, 1H),7.47-7.42 (m, 2H), 7.42-7.33 (m, 4H), 7.26-7.23 (m, 1H), 7.11-7.09 (m,1H), 6.96-6.90 (m, 2H), 4.84-4.77 (m, 1H), 3.23-3.10 (m, 2H).

Example 140

(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[1-(3,4-dichlorobenzyl)-2-oxo-2-piperidin-1-yl-ethyl]-benzamide

The title compound (37 mg, 66%) was prepared from(S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid and piperidine as in Example 1, Part C. HPLC: R_(T)=11.00 min. MS(ESI−): mass calcd. for C₂₇H₂₄Cl₃N₅O₄S₂, 653.00; m/z found, 650/652[M−H]⁻. ¹H NMR (500 MHz, CDCl₃): 11.70 (m, 1H), 8.38 (d, J=7.0, 1H),8.21 (d, J=8.8, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.69 (d, J=1.9, 1H),7.35 (d, J=8.2, 1H), 7.28-7.25 (m, 1H), 7.22 (d, J=1.9, 1H), 7.13 (d,J=7.4, 1H), 6.99 (dd, J=8.2 1.9, 1H), 6.92 (dd, J=8.4, 1.9, 1H),5.26-5.21 (m, 1H), 3.62-3.49 (m, 2H), 3.43-3.35 (m, 1H), 3.26-3.19 (m,1H), 3.08-2.95 (m, 2H), 1.70-1.46 (m, 5H), 1.33-1.23 (m, 1H).

Example 141

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid

The title compound was prepared as in EXAMPLE 1, substituting2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl esterhydrochloride (prepared as in Example 2, Part A) and2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid inPart C. HPLC: R_(T)=10.48 min. MS (ESI−): mass calcd. forC₂₂H₁₄Cl₄N₄O₅S₂, 620.31; m/z found, 617/619/621 [M−H]⁻. ¹H NMR (400 MHz,acetone-d₆): 11.64 (s, 1H), 8.53 (s, 2H), 8.46 (d, J=7.0, 1H), 8.29 (d,J=8.7, 1H), 7.89 (dd, J=8.8, 7.1, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.56(d, J=1.8, 1H), 7.49 (d, J=8.2, 1H), 7.34 (dd, J=8.2, 1.8, 1H),5.00-4.94 (m, 1H), 3.40-3.36 (m, 1H), 3.25-3.17 (m, 1H).

Example 142

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid methyl ester

The title compound was prepared as in EXAMPLE 4, substituting3-bromo-4-chlorobenzyl bromide in Part B, substituting2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoic acid in PartE, and eliminating the LiOH hydrolysis step in Part E. HPLC: R_(T)=10.67min. MS (ESI−): mass calcd. for C₂₃H₁₇Br₂ClN₄O₅S₂, 688.80; m/z found,687/689 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 11.42 (s, 1H), 8.36 (dd, J=7.0,0.9, 1H), 8.22 (dd, J=8.8, 0.9, 1H), 7.88 (d, J=1.7, 1H), 7.73 (dd, J8.8, 7.1, 1H), 7.35-7.32 (m, 1H), 7.18-7.05 (m, 2H), 6.96 (dd, J=8.2,2.0, 1H), 6.57 (d, J=7.0, 1H), 4.97-4.92 (m, 1H), 3.82 (s, 3H),3.25-3.09 (m, 2H).

Example 143

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid methyl ester

A. 2-Acetylamino-3-(3-bromo-4-fluoro-phenyl)-acrylic acid. A mixture of3-bromo-4-fluorobenzaldehyde (50.0 g, 0.25 mol), N-acetylglycine (26.2g, 0.22 mol), NaOAc (13.8 g, 0.56 mol), and Ac₂O (52 mL) was heated at130° C. for 10 h in a flask fitted with a reflux condenser. Theresulting precipitate was collected by filtration, washed with water,and suspended in AcOH (250 mL). This mixture was heated at 100° C. for 1h in a flask fitted with a reflux condenser, and then was cooled to 0°C. The solids were collected by filtration, washing with water, to givethe product as a yellow solid (53.5 g, 76%). MS (ESI−): mass calcd. forC₁₁H₉BrFNO₃, 301.0; m/z found, 299.9[M−H]⁻. ¹H NMR (400 MHz, DMSO-d₆):12.80 (br s, 1H), 9.52 (br s, 1H), 7.93 (dd, J=6.9, 1.9, 1H), 7.66 (ddd,J=8.4, 4.8, 1.9, 1H), 7.42 (t, J=8.7, 1H), 7.19 (s, 1H), 1.98 (s, 3H).

B. (S)-2-Acetylamino-3-(3-bromo-4-fluoro-phenyl)-propionic acid. Amixture of bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate(0.11 g, 0.18 mmol) and(R)-N-diphenylphosphino-N-methyl-1-[(S)-2-diphenylphosphino)ferrocenyl]ethylamine[(R)-methyl BoPhoz; 70 mg, 0.15 mmol] in MeOH (150 mL) under N₂ wasstirred for 30 min. 2-Acetylamino-3-(3-bromo-4-fluoro-phenyl)-acrylicacid (4.5 g, 15 mmol) was added, and the mixture was stirred under H₂(40 psi) on a Parr apparatus for 18 h. The mixture was concentrated togive the title compound as an orange oil (4.5 g, 100%). MS (ESI−): masscalcd. for C₁₁H₁₁BrFNO₃, 303.0; m/z found, 301.8 [M−H]⁻. ¹H NMR (400MHz, DMSO-d₆): 7.50 (dd, J=6.7, 2.1, 1H), 7.24(ddd, J=8.4, 4.7, 2.2,1H), 7.13 (t, J=8.6, 1H), 4.65(dd, J=9.0, 5.2, 1H), 3.19 (dd, J=14.0,5.2, 1H), 2.93 (dd, J=14.0, 9.0, 1H), 1.93 (s, 3H).

C. 3-Bromo-4-fluoro-L-phenylalanine hydrochloride. A suspension of(S)-2-acetylamino-3-(3-bromo-4-fluoro-phenyl)-propionic acid (2.5 g, 8.2mmol) in HCl (6.0 M in water, 5.0 mL) was heated at 100° C. for 2 h andthen cooled to 0° C. The resulting solid was collected by filtration togive the title phenylalanine as a light tan solid (2.1 g, 86%). MS(ESI+): mass calcd. for C₉H₉BrFNO₂, 261.0; m/z found, 261.8 [M+H]⁺. ¹HNMR (400 MHz, D₂O): 7.50 (dd, J=6.6, 2.1, 1H), 7.21 (ddd, J=8.4, 4.7,2.2, 1H), 7.14 (t, J=8.7, 1H), 3.90 (dd, J=7.7, 5.5, 1H), 3.16 (dd,J=14.7, 5.4, 1H), 3.04 (dd, J=14.7, 7.7, 1H).

D. 3-Bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride.3-Bromo-4-fluoro-L-phenylalanine hydrochloride was converted to themethyl ester as described in EXAMPLE 2, Part A.

E.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid methyl ester. The title compound was prepared as in EXAMPLE 1,substituting 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochlorideand 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoic acid inPart C. HPLC: R_(T)=10.39 min. MS (ESI−): mass calcd. forC₂₃H₁₇Br₂FN₄O₅S₂, 672.34; m/z found, 671 [M−H]⁻. ¹H NMR (400 MHz,CDCl₃): 11.42 (s,1H), 8.37 (d, J=7.1, 1H), 8.22 (d, J=8.8, 1H), 7.88 (s,1H), 7.75-7.71 (m, 1H), 7.27-7.25 (m, 1H), 7.11 (q, J=8.4, 2H),7.09-6.94 (m, 2H), 6.56 (d, J=7.0, 1H), 4.94 (q, J=5.8, 1 H), 3.82 (s,3H), 3.25-3.11 (m, 2H).

Example 144

(Z)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3,4-dichloro-phenyl)-acrylicacid

To a solution of2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionicacid methyl ester 42 mg, 0.068 mmol) in DCM (1.5 mL) was added Et₃N (38μL, 0.273 mmol) and the mixture was cooled to 0° C. MsCl (8 μL, 0.102mmol) was added and the mixture was warmed to rt and stirred for 1.5 h.The mixture was heated to 50° C., treated with catalytic DMAP, andstirred overnight. The mixture was diluted with satd. aq. NaHCO₃ andextracted with DCM (3×). The combined organic layers were dried (MgSO₄)and concentrated to provide2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3,4-dichloro-phenyl)-acrylicacid methyl ester. The crude product was hydrolyzed as in Example 2,Part E, to provide the title compound (25% for two steps). HPLC:R_(T)=9.97 min. MS (ESI−): mass calcd. for C₂₂H₁₅Cl₃N₄O₅S₂, 618.30; m/zfound, 581/583 [M−H]⁻. ¹H NMR (400 MHz, acetone-d₆): 11.82 (s, 1H), 9.37(d, J=5.1, 1H), 8.48 (d, J=7.1, 1H), 8.34 (dd, J=8.8, 0.9, 1H),7.96-7.86 (m, 2H), 7.82-7.75 (m, 2H), 7.64-7.55 (m, 3H), 7.11 (dd,J=8.5, 2.0, 1H).

Example 145

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid was prepared from 3-bromo-4-chloro-L-phenylalanine methyl esterhydrochloride and2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid as inEXAMPLE 1, Part C. Hydrolysis of the methyl ester as in EXAMPLE 2, PartE, provided the title compound. HPLC: R_(T)=10.07 min. MS (ESI−): masscalcd. for C₂₂H₁₅BrCl₂N₄O₅S₂, 630.32; m/z found, 629/631 [M−H]⁻. ¹H NMR(400 MHz, CDCl₃): 11.35 (s, 1H), 8.36 (d, J=7.0, 1H), 8.20 (d, J=8.8,1H), 7.76-7.69 (m, 2H), 7.41 (d, J=1.7, 1H), 7.36 (d, J=8.2, 1H), 7.17(d, J=8.5, 1H), 7.05 (dd, J=8.2, 1.8, 1H), 6.91 (dd, J=8.4, 1.8, 1H),6.53 (d, J=7.1, 1H), 5.04-4.95 (m, 1H), 3.36-3.15 (m,2H).

Example 146

(S)-3-(3-Bromo-4-chloro-phenyl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid

(S)-3-(3-Bromo-4-chloro-phenyl)-2-14-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid was prepared from 3-bromo-4-chloro-L-phenylalanine methyl esterhydrochloride and 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acidas in Example 1, Part C. Hydrolysis of the methyl ester as in EXAMPLE 2,Part E, provided the title compound. HPLC: R_(T)=9.80 min. MS (ESI−):mass calcd. for C₂₄H₁₇BrCl₂N₄O₅S, 624.29; m/z found, 621/623/625 [M−H]⁻.¹H NMR (400 MHz, CDCl₃): 11.04 (s, 1H), 8.98 (d, J=1.6, 1H), 8.90 (d,J=1.6, 1H), 8.54 (dd, J=7.3, 1.0, 1H), 8.28 (dd, J=8.4, 0.9, 1H),7.91-7.86 (m,1H), 7.71 (d, J=1.9, 1H), 7.43 (d, J=1.8, 1H), 7.33 (d,J=8.2, 1H), 7.13 (d, J=8.4, 1H), 7.05 (dd, J=8.2, 1.9, 1H), 6.86 (dd,J=8.4, 1.9, 1H), 6.53 (d, J=7.5, 1H), 4.91 (q, J=6.2, 1H), 3.34-3.09 (m,2H).

Example 147

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid was prepared from 3-bromo-4-chloro-L-phenylalanine methyl esterhydrochloride and 4-chloro-2-quinoxaline-5-sulfonylamino)-benzoic acidas in Example 1, Part C. Hydrolysis of the methyl ester as in EXAMPLE 2,Part E, provided the title compound. HPLC: R_(T)=10.43 min. MS (ESI−):mass calcd. for C₂₂H₁₄BrCl₃N₄O₅S₂, 664.76; m/z found, 661/663/665[M−H]⁻.¹H NMR (400 MHz, CDCl₃): 11.12 (s, 1H), 8.34 (d, J=7.0, 1H), 8.19 (d,J=8.8, 1H), 7.77 (S, 1H), 7.71 (dd, J=8.6, 7.2, 1H), 7.43 (d, J=1.7,1H), 7.36-7.31 (m, 2H), 7.07 (dd, J=8.2, 1.6, 1H), 6.78 (d, J=7.3, 1H),4.97 (q, J=6.3, 1H), 3.32-3.14 (m, 2H).

Example 148

(S)-3-(3-Bromo-4-chloro-phenyl)-2-[4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid

(S)-3-(3-Bromo-4-chloro-phenyl)-2-[4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid was prepared from 3-bromo-4-chloro-L-phenylalanine methyl esterhydrochloride and 4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoicacid (prepared from quinoxaline-5-sulfonyl chloride as in EXAMPLE 14,Part A) as in Example 1, Part C. Hydrolysis of the methyl ester as inEXAMPLE 2, Part E, provided the title compound. HPLC: R_(T)=10.21 min.MS (ESI−): mass calcd. for C₂₄H₁₆BrCl₃N₄O₅S, 658.74; m/z found,655/657/659 [M−H]⁻. ¹H NMR (400 MHz, CDCl₃): 10.83 (s, 1H), 8.98 (d,J=1.8, 1H), 8.92 (d, J=1.7, 1H), 8.52 (dd, J=7.3, 1.2, 1H), 8.30 (dd,J=8.5, 1.3, 1H), 7.88 (d, J=7.5, 1H), 7.85 (s, 1H), 7.43-7.42 (m, 1H),7.37-7.34 (m, 1H), 7.07-7.02 (m, 1H), 6.47 (d, J=7.6, 1H), 4.91-4.85 (m,1H), 3.24-3.09 (m, 2H).

Example 149

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid methyl ester

The title compound was prepared from 3-bromo-4-fluoro-L-phenylalaninemethyl ester hydrochloride and2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid as inExample 1, Part C. HPLC: R_(T)=10.36 min. MS (ESI−): mass calcd. forC₂₃H₁₇BrClFN₄O₅S₂, 627.89; m/z found, 625/627 [M−H]⁻. ¹H NMR (400 MHz,CDCl₃): 11.46 (s, 1H), 8.37 (dd, J=7.0, 0.8, 1H), 8.22 (dd, J=8.8, 0.9,1H), 7.75-7.68 (m, 2H), 7.32-7.14 (m, 2H), 7.09-6.88 (m, 3H), 6.53 (d,J=6.8, 1H), 4.98-4.90 (m, 1H), 3.82 (s, 3H), 3.24-3.10 (m, 2H).

Example 150

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid methyl ester

The title compound was prepared from 3-bromo-4-fluoro-L-phenylalaninemethyl ester hydrochloride and2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichlorobenzoic acid asin Example 1, Part C. HPLC: R_(T)=10.74 min. MS (ESI−): mass calcd. forC₂₃H₁₆BrCl₂FN₄O₅S₂, 662.34; m/z found, 659/661 [M−H]⁻. ¹H NMR (500 MHz,CDCl₃): 11.16 (s, 1H), 8.36 (dd, J=7.1, 0.8, 1H), 8.24 (dd, J=8.8, 0.8,1H), 7.86 (s, 1H), 7.74 (dd, J=8.8, 7.1, 1H), 7.33 (s, 1H), 7.30-7.27(m, 1H), 7.06 (t, J=8.3, 1H), 7.03-6.98 (m, 1H), 6.53 (d, J=7.1, 1H),4.93 (q, J=5.8, 1H), 3.22 (s, 3H), 3.24-3.11 (m, 2H).

Example 151

(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-bromo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester

The title compound was prepared from 3-bromo-4-fluoro-L-phenylalaninemethyl ester hydrochloride and4-bromo-2-(quinoxaline-5-sulfonylamino)-benzoic acid (EXAMPLE 8, PartsA-E, substituting 2-amino-4-bromo-benzoic acid methyl ester in Part D)as in Example 1, Part C. HPLC: R_(T)=10.11 min. MS (ESI−): mass calcd.for C₂₅H₁₉Br₂FN₄O₅S, 666.31; m/z found, 665/667 [M−H]⁻. ¹H NMR (400 MHz,CDCl₃): 11.19 (s, 1H), 8.98 (d, J=1.5, 1H), 8.92 (d, J=1.4, 1H), 8.58(d, J=7.3, 1H), 8.33 (d, J=8.5, 1H), 7.94-7.86 (m, 2H), 7.25 (d, J=1.9,1H), 7.12-6.92 (m, 4H), 6.45 (d, J=7.1, 1H), 4.92 (q, J=5.7, 1H), 3.81(s, 3H), 3.22-3.09 (m, 2H).

Example 152

(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester

The title compound was prepared from 3-bromo-4-fluoro-L-phenylalaninemethyl ester hydrochloride and4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in Example 1,Part C. HPLC: R_(T)=10.09 min. MS (ESI−): mass calcd. forC₂₅H₁₉BrClFN₄O₅S, 621.86; m/z found, 619/621 [M−H]⁻. ¹H NMR (400 MHz,CDCl₃): 11.24 (s, 1H), 8.98 (d, J=1.6, 1H), 8.92 (d, J=1.6, 1H), 8.58(dd, J=7.3, 1.1, 1H), 8.33 (dd, J=8.5, 1.1, 1H), 7.92-7.86 (m, 1H), 7.76(d, J=1.9, 1H), 7.28-7.25 (m, 1H), 7.19 (d, J=8.4, 1H), 7.06-6.94 (m,2H), 6.92 (dd, J=8.4, 1.9, 1H), 6.48 (d, J=7.2, 1H), 4.92 (q, J=5.7,1H), 3.81 (s, 3H), 3.22-3.09 (m, 2H).

Example 153

(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester

The title compound was prepared from 3-bromo-4-fluoro-L-phenylalaninemethyl ester hydrochloride and4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid (prepared fromquinoxaline-5-sulfonyl chloride as in EXAMPLE 14, Part A) as in Example1, Part C. HPLC: R_(T)=10.50 min. MS (ESI−): mass calcd. forC₂₅H₁₈BrCl₂FN₄O₅S, 656.31; m/z found, 653/655/657 [M−H]⁻. ¹H NMR (400MHz, CDCl₃): 10.99 (s,1H), 8.96 (d, J=1.7, 1H), 8.93 (d, J=1.7, 1H),8.55 (dd, J=7.3, 1.1, 1H), 8.33 (dd, J=8.5, 1.1, 1H), 7.91-7.85 (m, 2H),7.31-7.22 (m, 2H), 7.07-6.94 (m, 2H), 6.52 (d, J=7.3, 1H), 4.89 (q,J=5.8, 1H), 3.81 (s, 3H), 3.21-3.08 (m, 2H).

Example 154

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid methyl ester

The title compound was prepared from2-amino-3(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride(prepared as in Example 2, Part A) and2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid as inExample 1, Part C. HPLC: R_(T)=10.50 min. MS (ESI−): mass calcd. forC₂₂H₁₅Cl₃N₄O₅S₂, 691.35; m/z found, 689/691 [M−H]⁻. ¹H NMR (400 MHz,CDCl₃): 11.34 (s,1H), 8.36 (dd, J=7.1, 0.9, 1H), 8.23 (dd, J=8.8, 0.9,1H), 8.08 (d, J=1.5, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.36-7.30 (m, 2H),7.14 (d, J=2.0, 1H), 6.95 (d, J=8.3, 1H), 6.90 (dd, J=8.2, 2.0, 1H),6.53 (d, J=7.0, 1H), 4.94 (q, J=5.6, 1H), 3.82 (s, 3H), 3.25-3.10 (m,2H).

Example 155

(S)-3-(3-Bromo-4-chloro-phenyl)-2-[4-bromo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid

The title compound was prepared from 3-bromo-4-chloro-L-phenylalaninemethyl ester hydrochloride and4-bromo-2-(quinoxaline-5-sulfonylamino)-benzoic acid (EXAMPLE 8, PartsA-E, substituting 2-amino-4-bromo-benzoic acid methyl ester in Part D)as in Example 1, Part C, followed by hydrolysis of the resulting methylester as in EXAMPLE 2, Part E. HPLC: R_(T)=9.86 min. MS (ESI−): masscalcd. for C₂₂H₁₅Cl₃N₄O₅S₂, 668.74; m/z found, 665/667/669 [M−H]⁻. ¹HNMR (400 MHz, CDCl₃): 11.01 (s, 1H), 9.00 (s, 1H), 8.92 (s,1H), 8.-55(d, J=7.2, 1H), 8.30 (d, J=8.4, 1H), 7.94-7.85 (m, 2H), 7.42 (s, 1H),7.34 (d, J=8.1, 1H), 7.10-6.99 (m, 3H), 6.43 (d, J=7.0, 1H), 4.95-4.87(m, 1H), 3.29-3.10 (m, 2H).

Example 156

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid

The title compound was prepared from 3-bromo-4-fluoro-L-phenylalaninemethyl ester hydrochloride and2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid as inEXAMPLE 1, Part C, followed by hydrolysis of the resulting methylesteras in EXAMPLE 2, Part E. HPLC: R_(T)=9.72 min. MS (ESI−): mass calcd.for C₂₂H₁₅BrClFN₄O₅S₂, 613.87; m/z found, 611/613 [M−H]⁻. ¹H NMR (400MHz, CDCl₃): 11.36 (s, 1H), 8.34 (d, J=6.9, 1H), 8.16(d, J=8.7, 1H),7.74-7.67 (m, 1H), 7.66-7.63 (m, 1H), 7.38-7.32 (m, 1H), 7.20-7.15 (m,1H), 7.12-7.05 (m, 1H), 7.05-6.98 (m, 1H), 6.91-6.84 (m, 1H), 6.68 (d,J=6.7, 1H), 6.09 (s, 2H), 5.04-4.94 (m, 1H), 3.35-3.15 (m, 2H).

Example 157

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid

The title compound was prepared from 3-bromo-4-fluoro-L-phenylalaninemethyl ester hydrochloride and2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid asin Example 1, Part C, followed by hydrolysis of the resulting methylester as in EXAMPLE 2, Part E. HPLC: R_(T)=10.10 min. MS (ESI−): masscalcd. for C₂₂H₁₄BrCl₂FN₄O₅S₂, 648.31; m/z found, 645/647/649 [M−H]⁻. ¹HNMR (400 MHz, acetone-d₆): 11.58 (s, 1H), 8.47-8.42 (m, 1H), 8.34-8.20(m, 2H), 7.92-7.85 (m, 1H), 7.85-7.80 (m, 1H), 7.75-7.70 (m, 1H),7.67-7.60 (m, 1H), 7.42-7.35 (m, 1H), 7.25-7.18 (m, 1H), 4.96-4.87 (m,1H), 3.40-3.32 (m, 1H), 3.20-3.10 (m, 1H).

Example 158

(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-bromo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid

The title compound was prepared from 3-bromo-4-fluoro-L-phenylalaninemethylester hydrochloride and4-bromo-2-(quinoxaline-5-sulfonylamino)-benzoic acid (EXAMPLE 8, PartsA-E, substituting 2-amino-4-bromo-benzoic acid methyl ester in Part D)as in Example 1, Part C, followed by hydrolysis of the resulting methylester as in EXAMPLE 2, Part E. HPLC: R_(T)=9.52 min. MS (ESI−): masscalcd. for C₂₄H₁₇Br₂FN₄O₅S, 652.29; m/z found, 649/651/653 [M−H]⁻. ¹HNMR (400 MHz, acetone-d₆): 11.64 (s,1H), 8.99-8.93 (m, 2H), 8.62-8.57(m,1H), 8.37-8.31 (m, 1H), 8.07-7.98 (m, 2H), 7.94-7.90 (m,1H),7.65-7.59 (m, 1H), 7.51-7.45 (m, 1H), 7.41-7.34 (m, 1H), 7.23-7.16 (m,1H), 7.14-7.08 (m, 1H), 5.00-4.90 (m, 1H), 3.37-3.29 (m, 1H), 3.18-3.09(m, 1H).

Example 159

(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid

The title compound was prepared from 3-bromo-4-fluoro-L-phenylalaninemethyl ester hydrochloride and4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in Example 1,Part C, followed by hydrolysis of the resulting methyl ester as inEXAMPLE 2, Part E. HPLC: R_(T)=9.46 min. MS (ESI−): mass calcd. forC₂₄H₁₇BrClFN₄O₅S, 607.84; m/z found, 605/607 [M−H]⁻. ¹H NMR (400 MHz,acetone-d₆): 11.66 (s, 1H), 8.99-8.93 (m, 2H), 8.63-8.57 (m, 1H),8.37-8.31 (m, 1H), (m, 2H), 7.78-7.75 (m, 1H), 7.65-7.60 (m, 1H),7.58-7.53 (m, 1H), 7.41-7.34 (m, 1H), 7.24-7.17 (m, 1H), 6.97 (dd,J=8.3, 1.6, 1H), 5.00-4.92 (m, 1H), 3.37-3.28 (m, 1H), 3.18-3.10 (m,1H).

Example 160

(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid

The title compound was prepared from 3-bromo-4-fluoro-L-phenylalaninemethyl ester hydrochloride and4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid (prepared fromquinoxaline-5-sulfonyl chloride as in EXAMPLE 14, Part A) as in Example1, Part C, followed by hydrolysis of the resulting methyl ester as inExample 2, Part E. HPLC: R_(T)=9.91 min. MS (ESI−): mass calcd. forC₂₄H₁₆BrCl₂FN₄O₅S, 642.28; m/z found, 639/641/643 [M−H]⁻. ¹H NMR (400MHz, acetone-d₆): 11.49 (s, 1H), 9.00-8.93 (m, 2H), 8.62-8.57 (m, 1H),8.37-8.32 (m, 1H), 8.20-8.12 (m, 1H), 8.05-7.97 (m, 1H), 7.93-7.88 (m,1H), 7.73-7.67 (m, 1H), 7.65-7.61 (m, 1H), 7.41-7.33 (m, 1H), 7.25-7.15(m, 1H), 5.00-4.90 (m, 1H), 3.38-3.28 (m, 1H), 3.18-3.10 (m, 1H).

Example 161

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid

The title compound was prepared from 3-bromo-4-chloro-L-phenylalaninemethyl ester hydrochloride and2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromobenzoic acid as inExample 1, Part C, followed by hydrolysis of the resulting methyl esteras in EXAMPLE 2, Part E. HPLC: R_(T)=10.05 min. MS (ESI−): mass calcd.for C₂₂H₁₅Br₂ClN₄O₅S₂, 674.77; m/z found, 673/675 [M−H]⁻. ¹H NMR (400MHz, acetone-d₆): 11.77 (s,1H), 8.46-8.42 (m,1H), 8.34-8.29 (m,1H),8.19-8.13 (m,1H), 7.93-7.87 (m, 1H), 7.87-7.82 (m, 1H), 7.73-7.69 (m,1H), 7.54-7.46 (m, 2H), 7.40-7.35 (m, 1H), 7.17-7.12 (m, 1H), 4.97-4.88(m, 1H), 3.40-3.32 (m, 1H), 3.22-3.14 (m, 1H).

Example 162

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid

The title compound was prepared from 3-bromo-4-fluoro-L-phenylalaninemethyl ester hydrochloride and2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoic acid as inExample 1, Part C, followed by hydrolysis of the resulting methyl esteras in EXAMPLE 2, Part E. HPLC: R_(T)=9.75 min. MS (ESI−): mass calcd.for C₂₂H₁₅Br₂FN₄O₅S₂, 658.32; m/z found, 655/657/659 [M−H]⁻. ¹H NMR (400MHz, acetone-d₆): 11.76 (s, 1H), 8.46-8.41 (m, 1H), 8.32-8.27 (m, 1H),8.16-8.09 (m, 1H), 7.93-7.82 (m, 2H), 7.66-7.60 (m, 1H), 7.53-7.47 (m,1H), 7.41-7.34 (m, 1H), 7.24-7.11 (m, 2H), 4.95-4.86 (m, 1H), 3.39-3,31(m, 1H), 3.21-3.12 (m, 1H).

Example 163

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid ethyl ester

The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanineethyl ester hydrochloride and2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid asin Example 1, Part C. HPLC: R_(T)=10.96 min. MS (ESI−): mass calcd. forC₂₂H₁₅Cl₃N₄O₅S₂, 676.36; m/z found, 673/675[M−H]⁻. ¹H NMR (400 MHz,CDCl₃): 11.20 (s, 1H), 8.36 (dd, J=7.0, 0.8, 1H), 8.23 (dd, J=8.8, 0.9,1H), 7.86 (s, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.34 (s, 1H), 7,29 (dd,J=6.5, 1.9, 1H), 7.07-6.99 (m, 2H), 6.59 (d, J=7.0, 1H), 4.89 (q, J=5.8,1H), 4.27 (q, J=7.1, 2H), 3.17 (d, J=5.8, 1H), 1.33 (t, J=7.2, 3H).

The racemic compounds in Examples 164-173 may be prepared according tothe methods described above.

Example 164

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid

Example 165

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-3-iodo-phenyl)-propionicacid

Example 166

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid

Example 167

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionicacid

Example 168

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyricacid

Example 169

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide

Example 170

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide

Example 171

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionicacid

Example 172

2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyricacid

Example 173

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-4-chloro-benzamide

Example 174

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid tert-butyl ester

A. (S)-2-(Benzhydrylidene-amino)-3-(3-bromo-4-fluoro-phenyl)-propionicacid tert-butyl ester. To a flame-dried flask was added(benzhydrylidene-amino)-acetic acid tert-butyl ester (250 mg, 0.846mmol), O-allyl-N-(9-anthracenylmethyl)-cinchonidinium bromide (51 mg,0.085 mmol), and DCM (5 mL). The flask was cooled to −55° C. andCsOH.H₂O (1.4 g, 8.46 mmol) was added. The mixture was stirred for 30min, treated with 3-bromo-4-fluorobenzyl bromide (1.1 g, 4.23 mmol), andstirred at −55° C. overnight. The mixture was diluted with Et₂O (5 mL)and water (10 mL), warmed to rt, and washed with water and brine. Theorganic layer was dried (MgSO₄) and concentrated. The residue waspurified by column chromatography to provide the title compound (300 mg,74%, er=97:3). MS (ESI+): mass calcd. for C₂₆H₂₅BrFNO₂, 482.4; m/zfound, 483.4 {M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.59-7.54 (m, 2H),7.41-7.20 (m, 7H), 7.02-6.91 (m, 2H), 6.72 (d, J=6.5 Hz, 2H), 4.11-4.07(m, 1H), 3.19-3.08 (m, 2H), 1.45 (s, 9H).

B. (S)-2-Amino-3-(3-bromo-4-fluoro-phenyl)-propionic acid tert-butylester. A solution of(S)-2-(benzhydrylidene-amino)-3-(3-bromo-4-fluoro-phenyl)-propionic acidtert-butyl ester (300 mg, 0.622 mmol) in THF (3 mL) was treated with 10%citric acid (3 mL). The mixture was stirred overnight, diluted withwater, and extracted with Et₂O (2×). The aqueous layer was basified topH=10 with satd. aq. K₂CO₃ and extracted with EtOAc (3×). The combinedorganic layers were dried (MgSO₄) and concentrated to give the titlecompound (247 mg, 64%). MS (ESI+): mass calcd. for C₁₃H₁₇BrFNO₂, 318.18;m/z found, 262.2 [M−t−Bu]⁺. ¹H NMR (400 MHz, CDCl₃): 7.42 (dd, J=6.6,2.1 Hz, 1H), 7.16-7.11 (m, 1H), 7.08-7.02 (m, 1H), 3.56 (dd, J=7.3, 5.9Hz, 1H), 2.85-2.78 (m, 1H), 2.99-2.92 (m, 1H), 1.43 (m, 9H).

C.(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4.5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid tert-butyl ester. The title compound may be prepared as describedin Example 1, Part C.

The compounds in Examples 175-176 may be prepared according to themethods described above.

Example 175

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid 2-morpholin-4-yl-ethyl ester

Example 176

(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3(3-bromo-4-fluoro-phenyl)-propionicacid dimethylcarbamoylmethyl ester.

Intermediate 1

Preparation of 3-bromo-4-chloro-L-phenylalanine

A. 3-Bromo-4-chlorobenzyl chloride. To a solution of3-bromo-4-chlorobenzyl alcohol (9.6 g, 43 mmol) in CH₂Cl₂ (100 mL) wasadded Ph₃P (17.1 g, 1.5 mmol) and CCl₄ (6.3 mL, 65 mmol). After 18 h,the solution was washed with brine (3×100 mL) and passed through a shortsilica gel column to afford the product as,colorless oil (9.14 g, 88%).¹H NMR (400 MHz, CDCl₃): 7.65 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H),7.27 (dd, J=8.3, 2.1 Hz, 1H), 4.51 (s, 3H).

B. 3-Bromo-4-chloro-L-phenylalanine. To a solution of2-acetylamino-malonic acid diethyl ester (15.1 g, 70 mmol) and3-bromo-4-chlorobenzyl chloride (16.7 g, 70 mmol) in EtOH (110 mL) wasadded a solution of NaOEt (20% in EtOH, 28.7 mL, 73 mmol). The mixturewas heated at reflux for 3 h in a flask filted with a reflux condenser,then was treated with additional 2-acetylamino-malonic acid diethylester (3.0 g, 14 mmol) and NaOEt (20% in EtOH, 2.0 mL, 5.1 mmol). Themixture was heated at reflux for an additional 3 h. The mixture wascooled to rt and treated with water (200 mL). The resulting whiteprecipitate was collected by filtration, washed with water, andsuspended in a mixture of water (60 mL) and EtOH (60 mL). This mixturewas heated to reflux temperature in a flask fitted with a refluxcondenser. A solution of KOH 43,3 g, 59 mmol) in water (10 mL) was addeddropwise. After 2 h at reflux, more KOH (5.9 g, 105 mmol) in water (20mL) was added dropwise, and the mixture was heated at reflux for 3 h.The mixture was cooled to 0° C., diluted with water (120 mL), andtreated with 50% aq. HCl until pH˜1. The resulting white precipitate wascollected by filtration and washed with 0.1 M HCl. The solid wassuspended in water (80 mL) and treated with 2 M aq. KOH until pH˜8.0.The solution was filtered. The filtrate was warmed to 40° C., treatedwith Acylase “Amano” (0.19 g, Amano Enzyme Inc., Japan) and CoCl₂ (10mg), and 2 M aq. KOH was added to keep the pH of solution at 8.0. After4 d at 40° C., 2 M HCl was added until pH=1. The suspension was filteredand the filtrate was concentrated to 20 mL. The pH was adjusted to 6.0with 2.0 M KOH. The mixture was kept at 0° C. overnight and the solidwas collected by filtration to obtain the title compound as a light tansolid (7.67 g, 40% overall). ¹H NMR (400 MHz, DMSO-d₆): 7.66 (br s, 1H),7.51 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 3.39 (dd, J=7.1, 5.3 Hz,1H), 3.08 (dd, J=14.2, 4.6 Hz, 1H), 2.86 (dd, J=14.0, 7.7 Hz, 1H). Todetermine the enantiomeric ratio, the product was transformed to thecorresponding methyl ester (SOCl₂, MeOH, rt) and then to the Mosher'samide (Mosher's acid chloride, iPr₂NEt, CH₂Cl₂). The analysis of ¹H-NMRdata of the amide showed that the product was a single enantiomer (e.e.>99.5%).

C. The product from Step B may be used to prepare compounds of theinvention according to the methods described in the preceding examples.

Assay Methods

A. Binding Assays

1. CCK1 Assay Development and Data Generation

Cell Culture

CHO-K1 cells that had undergone stable transfection with the CCK-1receptor were grown in DMEM supplemented with L-glutamine (2 mM),penicillin (50 units/mL) and streptomycin (50 μg/mL). Cells werecultured under continuous G418-selection (2 mM) and were harvested usinga rubber cell scraper. CHO-K1 cells were sub-cultured a maximum of tentimes before being reseeded from the original stocks.

Membrane Preparation

Membranes were prepared from the stably transfected CHO-K1 cells. Frozencell pellets (−40° C) were thawed in 14 mL of buffer A (10 mM HEPES, 130mM NaCl, 4.7 mM KCl, 5 mM MgCl, 1 mM EGTA and 15.4 mg/100 mL-bacitracinat pH 7.2), adapted from Harper et al. (Br. J. Pharmacol. 1996,118:1717-1726). The thawed pellets were homogenized using a PolytronPT-LD (7×1 s). The homogenates were centrifuged for 5 min at 1500 rpm(600×g), and the resulting pellets were discarded. The supernatants wererecentrifuged in order to collect the receptor-membrane pellets (25 min15,000 rpm; 39,800×g), which were re-suspended in buffer A.

Incubation Conditions

All assays were conducted in 96-well plates (GF/B millipore filterplates) using buffer A, with 0.3 μM PD-134,308, for the dilutions. TheCCK-2 receptor ligand was included to eliminate the contribution of thisreceptor subtype to the binding. For the optimal cell numberdetermination experiments 20 pM [¹²⁵I]-BH-CCK-8S (50 μL 60 pM. solution)was incubated with a range of cell concentrations (2.5×105 to 12.5×105cells/well) in a total volume of 150 μL. Total binding of[¹²⁵I]-BH-CCK-8S was determined in the presence of 15 μL of buffer A.Non-specific binding of [¹²⁵I]-BH-CCK-8S was determined in the presenceof 15 μL of 100 μM 2-naphthalenesulphonyl L-aspartyl-(2-phenethyl)amide(2-NAP: see R. A. Hull et al. Br. J. Pharmacol. 1993, 108:734-740), aCCK-1 receptor selective antagonist that is structurally unrelated tothe radioligand [¹²⁵I]-BH-CCK-8S. The assay preparation was incubatedfor 1 h at 21±3° C., and then the assay was terminated upon rapidfiltration of the preparation under reduced pressure. The loaded filterswere washed three times using undiluted PBS (100 μL), and then theresidues were transferred to 5 mL scintillation tubes. Boundradioactivity was determined using a gamma counter (count time=1 min).From these experiments a cell concentration of 1 pellet in 40 mL ofbuffer (2.5×106 cells/mL) was chosen for use in other assays (below). Tovalidate the radioligand concentration and incubation time for theassay, saturation and kinetic binding studies were also conducted (seeM. F. Morton, The Pharmacological Characterization of CholecystokininReceptors in the Human Gastrointestinal Tract. PhD Thesis, University ofLondon, 2000). The affinity of novel compounds was estimated byincubating membrane preparations with 15 μL of competing ligand (0.1pM-1 mM) for 60 min at 21±3° C. The assay was then terminated accordingto the procedure outlined above.

2. CCK2 Assay Development and Data-Generation

Zinc Finger Proteins (ZFP) specific for the CCK2R gene were identifiedby Sangamo Biosciences. The ZFP domain was fused with the herpes simplexvirus VP16 activation domain, and the fusion protein was subsequentlycloned into the pcDNA3 mammalian expression vector (Invitrogen, SanDiego, Calif.). Tet-inducible cell lines expressing the coding regionfrom the ZFP vector were created using the T-REx-293™ cell line(Invitrogen). After 2 weeks of selection in culture medium containing400 mg/mL Zeocin (Invitrogen), sixty drug-resistant stable clones wereisolated and analyzed for ZFP expression as well as CCK2R induction uponaddition of doxycycline to the culture medium. The cell line with themost appropriate CCK2R ZFP construct was used in all further assays andwas termed the HEKZFP cell line.

Cell Culture

HEKZFP cells were grown in DMEM supplemented with L-glutamine (2 mM),penicillin (50 units/mL) and streptomycin (50 μg/mL) and 10% FBS (v/v).HEKZFP cells were treated with 2 mM doxycycline (Sigma-Aldrich, MO; USA)for 2 days to de-repress the tet-regulated expression of the CCK2receptor selective zinc finger proteins and were harvested using arubber cell scraper.

Membrane Preparation

Membranes were prepared from the HEKZFP cells after induction. Frozencell pellets (−40° C.) were thawed in 14 mL of buffer A (10 mM HEPES,130 mM NaCl, 4.7 mM KCl, 5 mM MgCl, 1 mM EGTA and 15.4 mg/100 mLbacitracin at pH 7.2), adapted from E. A. Harper et al. (Br. J.Pharmacol. (1996) 118(7):1717-1726). The thawed pellets were homogenizedusing a Polytron PT-10 (7×1 s). The homogenates were centrifuged for 5min at 1500 rpm (600×g), and the resulting pellets were discarded. Thesupernatants were re-centrifuged in order to collect thereceptor-membrane pellets (25 min 15,000 rpm; 39,800×g), which werere-suspended in buffer A.

Incubation Conditions

All assays were conducted in 96-well plates (GF/B millipore filterplates) using buffer A. For the optimal cell number determinationexperiments, cells in concentrations ranging from 2.5×10⁵ to 12.5×10⁵cells/well were incubated with 20 pM [¹²⁵I]-BH-CCK-8S (50 μL 60 pMsolution) in a total volume of 150 μL. Total binding of [¹²⁵I]-BH-CCK-8Swas determined in the presence of 15 μL of buffer A. Non-specificbinding of [¹²⁵I]-BH-CCK-8S was determined in the presence of 15 μL of10 μM YF476, a CCK-2 receptor selective antagonist that is structurallyunrelated to the radioligand [¹²⁵I]-BH-CCK-8S. The assay preparation wasincubated for 1 h at 21±3° C., and then the assay was terminated byrapid filtration of the preparation under reduced pressure. The loadedfilters were washed three times using undiluted PBS (100 μL), and then100 μL of scintillation fluid was added to the filter plate. Boundradioactivity was determined using a Topcount (Packard BioScience,Meriden, Conn.) with a count time of 1 min. From these experiments acell concentration of 1 pellet in 15 mL buffer was chosen for use inother assays. To validate the radioligand concentration and incubationtime for the assay, saturation and kinetic binding studies were alsoconducted (see M. F. Morton, The Pharrmacological Characterization ofCholecystokinin Receptors in the Human Gastrointestinal Tract. PhDThesis, University of London, 2000). The affinity of novel compounds wasestimated by incubating membrane preparations with 15 μL of competingligand (0.1 pM-1 mM) for 60 min at 21±3° C. The assay was thenterminated according to the procedure outlined above.

3. Data Analysis for CCK1 and CCK2 Binding Assays

The pKi values were determined using the equation of Y.-C. Cheng and W.H. Prusoff (Biochem. Pharmacol., 1973, 22(23):3099-3108):$K_{i} = \frac{{lC}_{50}}{1 + \frac{\lbrack L\rbrack}{K_{D}}}$

To circumvent problems associated with computer-assisted data analysisof compounds with low affinity, the data obtained in the current studywere weighted according to a method described by Morton. In brief, 100%and 0% specific binding were defined independently using total bindingand binding obtained in the presence of a high concentration of thereference antagonist, 2-NAP. Data for compounds tested are presented inTable 1. TABLE 1 EX CCK1 pK_(i) CCK2 pK_(i) 1 6.9 6.4 2 6.7 7.5 3 6.07.4 4 6.2 8.3 5 7.8 6.5 6 7.5 5.0 7 7.3 5.1 8 5.5 6.3 9 6.8 6.4 10 7.75.1 11 6.4 6.5 12 5.9 7.2 13 5.9 6.2 14 7.9 6.5 15 7.4 6.7 16 7.2 6.2 177.1 5.6 18 6.5 5.8 19 6.7 6.6 20 5.7 7.0 21 6.9 6.0 22 6.3 6.2 23 6.06.2 24 7.0 5.9 25 5.0 7.4 26 5.6 7.4 27 5.0 7.5 28 5.0 7.1 29 5.2 7.1 307.2 5.6 31 7.1 6.2 32 6.4 7.0 33 6.8 7.4 34 6.4 7.0 35 7.2 6.3 36 7.15.8 37 6.4 5.4 38 6.5 5.7 39 7.6 6.6 40 6.9 6.5 41 6.2 7.3 42 7.5 5.5 436.9 6.6 44 7.0 5.4 45 6.6 5.8 46 5.8 7.2 47 7.0 5.3 48 7.3 5.7 49 6.75.7 50 6.2 5.2 51 5.0 6.1 52 6.3 7.0 53 6.9 5.6 54 6.1 6.5 55 7.4 6.0 566.3 6.8 57 7.9 6.3 58 7.5 6.3 59 7.1 6.1 60 7.1 6.4 61 6.9 6.4 62 6.55.5 63 5.0 7.5 64 5.8 7.0 65 6.5 6.1 66 5.7 6.3 67 6.7 6.6 68 6.5 7.5 697.2 5.1 70 6.7 5.2 71 6.9 5.6 72 7.1 6.3 73 6.8 5.0 74 6.5 5.1 75 6.05.4 76 5.5 7.4 77 5.0 7.5 78 5.4 7.5 79 7.2 5.9 80 7.0 5.8 81 6.1 5.7 826.1 5.1 83 5.8 6.6 84 5.0 7.5 85 5.0 7.2 86 5.0 7.5 87 5.0 6.8 88 5.26.2 89 5.1 7.2 90 5.9 7.5 91 7.1 7.8 92 7.2 7.5 93 6.8 8.3 94 5.2 6.0 955.5 6.1 99 7.1 6.1 101 7.4 6.1 106 5.0 5.9 107 5.4 6.1 108 7.6 5.9 1156.4 7.1 116 6.9 5.7 117 6.6 7.8 118 7.1 6.3 119 6.3 6.7 120 7.1 6.0 1216.9 6.3 122 6.8 6.4 123 7.0 6.8 124 6.5 7.3 125 6.5 6.2 126 6.6 8.3 1276.7 7.1 128 7.0 6.2 129 7.0 6.2 130 6.4 6.5 131 6.8 7.8 132 6.6 7.8 1336.4 7.5 134 6.3 7.7 135 6.3 8.1 136 7.4 6.5 137 7.1 6.7 138 7.0 7.3 1397.1 6.2 140 6.9 6.5 141 7.0 7.2 142 6.8 6.2 143 6.8 6.7 144 6.3 7.3 1456.7 7.4 146 6.6 7.6 147 6.8 7.4 148 6.6 7.2 149 6.7 6.7 150 7.1 6.6 1516.1 6.9 152 6 6.8 153 6.7 6.6 154 6.8 6.6 155 7.0 8.0 156 6.6 8.0 1576.8 8.0 158 6.5 8.3 159 6.4 8.0 160 6.8 8.2 161 6.9 7.9 162 6.6 8.2 1636.9 6.4B. Guinea-pig Gastric Corpeal Muscle Assay

CCK2 receptor-mediated muscle contraction was measured in an isolatedmuscle-strip assay of guinea-pig gastric corpeal muscle according to themethods described by Roberts et al. (S. P. Roberts, E. A. Harper, G. F.Watt, V. P. Gerskowitch, R. A. Hull, N. P. Shankley, and J. W. Black,Br. J. Pharmaool., 1996,118(7):1779-1789). In brief, strips of musclewere dissected and suspended in isolated tissue organ baths for isotonicmuscle contraction recording. The baths, containing Krebs-Henseleitsolution, were maintained at 24° C. and gassed continuously with 95% O₂and 5% CO₂. CCK1 receptors known to be present in this assay wereblocked using a selective concentration of a suitable CCK1 receptorantagonist (e.g. 2-NAP). The effectiveness of the test compounds wasassessed by measuring their effect on contractile concentration-responsecurves obtained using a well-characterized surrogate for the hormonegastrin (pentagastrin). The title compound of Example 2 behaved as acompetitive antagonist in this assay with a pKB value of 8.8.

1. A compound of formula (I):

wherein X is C₁₋₂alkyl or a bond; R¹ is selected from the groupconsisting of a) naphthyl, phenyl, said phenyl optionally fused at twoadjacent carbon atoms to R^(f), R^(f) is a linear 3- to 5-memberedhydrocarbon moiety having 0 or 1 unsaturated bonds and having 0, 1 or 2carbon members which is a carbonyl, b) Ar⁶—, where Ar⁶ is a 6-memberedheteroaryl having carbon as a point of attachment, having 1 or 2heteroatom members which are —N═ and optionally benzo or pyrido fused,c) Ar⁵—, where Ar⁵ is a 5-membered heteroaryl having carbon as a pointof attachment, having 1 heteroatom member selected from the groupconsisting of O, S, >NH, and >NC₁₋₄alkyl, having 0 or 1 additionalheteroatom member which is —N═ and optionally benzo or pyrido fused, d)Ar⁶⁻⁶—, where Ar⁶⁻⁶ is phenyl having the point of attachment and fusedto a 6-membered heteroaryl having 1 or 2 heteroatom members which are—N═, e) Ar⁶⁻⁵—, where Ar⁶⁻⁵ is phenyl or pyridyl having the point ofattachment and fused to a 5-membered heteroaryl having 1 heteroatommember selected from the group consisting of O, S, >NH, and >NC₁₋₄alkyl,and having 0 or 1 additional heteroatom member which is —N═, where eachof a) to e) is substituted with 0, 1, 2, or 3 of R^(q), R^(q) isindependently selected from the group consisting of —C₁₋₄alkyl, hydroxy,fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, cyano,aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl,HO—C₁₋₄alkyl, C₁₋₄alkylO—C₁₋₄alkyl, HS—C₁₋₄alkyl, C₁₋₄alkylS—C₁₋₄alkyl,C₁₋₄alkoxy, and C₁₋₄alkylS—; R² is selected from the group consisting of—H, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₇cycloalkyl, and—C₃₋₇cycloalkenyl; R^(a) is, independently, selected from the groupconsisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl,furanyl, thiophenyl, benzyl, pyrrol-1-yl, —OH, —OC₁₋₆-alkyl,—OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl,—SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, cyano, nitro, —N(R^(y))R^(z)(wherein R^(y) and R^(z) are independently —H, —C₁₋₄alkyl, orC₁₋₆cycloalkylC₁₋₄alkyl), —(C═O)C₁₋₄alkyl, —SCF₃, halo, trifluoromethyl,—OCF₃, and —COOC₁₋₄alkyl, —COOH, or, alternatively, two adjacent R^(a),may be taken together with the carbons of attachment to form a fusedring selected from the group consisting of phenyl, pyridyl, andpyrimidinyl; alternatively, R² and one of R^(a) may be taken together as—CH₂— or >C═O to form a fused ring to the phenyl; R^(b) is selected fromthe group consisting of 2,4-difluoro, 2,6-difluoro, or alternatively,two adjacent R^(b) substituents at 2- and 3-positions may be takentogether to form a five- or six-membered heterocyclic ring selected fromthe group consisting of oxazole, thiazole, thiadiazole, [1,3]dioxole,and pyrazine; R^(c) is independently selected from the group consistingof hydrogen, —C₁₋₄alkyl, perhaloC₁₋₄alkyl, mono- or di-haloC₁₋₄alkyl,aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl,HO—C₁₋₄alkyl, HS—C₁₋₄alkyl, C₁₋₄alkylS—C₁₋₄alkyl,—C₀₋₂alkylCOOC₁₋₄alkyl, —C₀₋₂alkylCOOH, and —C₀₋₂alkylCON(R^(s))R^(t);—COO—C₀₋₂alkyl-ringA, and —COO—C₁₋₂alkyl-CON(R^(s))R^(t); R^(s) andR^(t) are independently selected from the group consisting of —H,—C₁₋₄alkyl, C₁₋₆cycloalkylC₁₋₄alkyl, phenyl, phenyl substituted withhalo, benzyl, benzyl substituted with halo, or alternatively, R^(s) andR^(t) taken together with their nitrogen of attachment form pyrrolidine,piperidine, or morpholine; ringA is selected from the group consistingof i) a 6-membered heteroaryl having carbon as a point of attachment andhaving 1 or 2 heteroatom members which are —N═; ii) a 5-memberedheteroaryl having carbon as a point of attachment, having 1 heteroatommember selected from the group consisting of O, S, >NH, and >NC₁₋₄alkyl,and having 0 or 1 additional heteroatom member which is —N═ ; and iii) a5- or 6-membered non-aromatic heterocycle having a carbon or nitrogen asa point of attachment, having 1 or 2 heteroatoms selected from the groupconsisting of O, S, and N, having 0 or 1 double-bonds, having 0 or 1carbon member replaced by a carbonyl, and optionally substituted with—C₁₋₄alkyl, —OH, or halo; R^(d) is independently selected from the groupconsisting of hydrogen, —C₁₋₄alkyl, —OH, —OC₁₋₆alkyl, HO—C₁₋₄alkyl,perhaloC₁₋₄alkyl, mono- or di-haloC₁₋₄alkyl, aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl, HS—C₁₋₄alkyl,C₁₋₄alkylS—C₁₋₄alkyl, and optionally substituted phenyl; or two R^(d)together can be ═O where at least one R^(c) is selected from the groupconsisting of —COOC₁₋₄alkyl, —COO-ringA, —COOH, —CON(R^(s))R^(t), and—COOC₁₋₂alkylCON(R^(s))R^(t); alternatively, one R^(c) and one R^(d) maybe taken together to form a double bond; and enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof.
 2. The compound of claim 1 wherein X is a bond.
 3. Thecompound of claim 1 wherein R¹ is selected from the group consisting ofa) phenyl, naphthyl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-1,2,3 or4-yl, optionally 5,6,7,8 or 9 oxo substituted,5,6,7,8-tetrahydro-naphthalen-1,2,3 or 4-yl, optionally 5,6,7 or 8 oxosubstituted, b) pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,quinolin-2,3 or 4-yl, isoquinolin-1,3 or 4-yl, quinazolin-2 or 4-yl,quinoxalin-2 or 3-yl, naphthyridinyl, c) furanyl, thiophenyl, 1-(H orC₁₋₄alkyl)pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl,isoxazolyl, isothiazolyl, benzofuran-2 or 3-yl, benzothiophen-2 or 3-yl,1-(H or C₁₋₄alky)-1H-indol-2 or 3-yl, 1-(H orC₁₋₄alkyl)-1H-benzimidazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl,1H-pyrrolopyridin-2 or 3-yl, d) quinolin-5,6,7 or 8-yl,isoquinolin-5,6,7 or 8-yl, quinazolin-5,6,7 or 8-yl, quinoxalin-5,6,7 or8-yl, and e) benzofuran-4,5,6 or 7-yl, benzothiophen-4,5,6 or 7-yl, 1-(Hor C₁₋₄alkyl)-1H-indol-4,5,6 or 7-yl, 1-(H orC₁₋₄alkyl)-1H-benzimidazol-4,5,6 or 7-yl, benzooxazol-4,5,6 or 7-yl,benzothiazol-4,5,6 or 7-yl, 1H-pyrrolopyridin-4,5,6 or 7-yl, where eachof a) to e) is substituted with 0, 1, 2, or 3 of R^(q).
 4. The compoundof claim 1 wherein R¹ is selected from the group consisting of phenyl,6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl optionally 5,6,7,8 or 9-oxosubstituted, naphthyl, pyridyl, furanyl, thiophenyl, andbenzothiophenyl, where each member is substituted with 0, 1, 2, or 3 ofR^(q).
 5. The compound of claim 1 wherein R¹ is selected from the groupconsisting of phenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 2,6-dichlorophenyl, 2,4,6-trichlorophenyl,2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,2,6-difluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-4-fluorophenyl,2-fluoro-4-bromophenyl, 2-fluoro-4-chlorophenyl, 3-bromo-4-chlorophenyl,3-bromo-4-fluorophenyl, 4-chloro-3-iodophenyl, 2-methylphenyl,4-methylphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl,2-methylsulfanylphenyl, 2-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-nitrophenyl, 3-cyanophenyl, 4-cyanophenyl,naphthyl, thiophen-3-yl, 5-bromothiophen-3-yl, and benzothiophen-3-yl.6. The compound of claim 1 wherein R^(f) is selected from the groupconsisting of —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂— and—(C═O)CH₂CH₂CH₂—.
 7. The compound of claim 1 wherein R^(q) is selectedfrom the group consisting of methyl, ethyl, propyl, t-butyl, hydroxy,fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, cyano, aminomethyl,methylaminomethyl, dimethylaminomethyl, hydroxymethyl, methoxymethyl,methylsulfanyl, methylsulfanylmethyl, methoxy, ethoxy, mercaptomethyl,and mercaptoethyl.
 8. The compound of claim 1 wherein R^(q) is selectedfrom the group consisting of methyl, fluoro, chloro, bromo, iodo,trifluoromethyl, nitro, and cyano.
 9. The compound of claim 1 wherein R²is selected from the group consisting of —H, methyl, ethyl, i-propyl,t-butyl, allyl, propargyl, cyclopropyl, cyclohexyl, and cyclopentenyl.10. The compound of claim 1 wherein R² and one of R^(a) are takentogether as —CH₂— or >C═O to form a fused ring to the phenyl.
 11. Thecompound of claim 1 wherein R² is —H or methyl.
 12. The compound ofclaim 1 wherein R^(a) is selected from the group consisting of methyl,ethyl, propyl, i-propyl, ethenyl, propenyl, cyclopropyl, cyclobutyl,phenyl, furanyl, thiophenyl, pyrrol-1-yl, benzyl, methoxy, ethoxy,propoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, iphenoxy, benzoxy,mercapto, methylsulfanyl, ethylsulfanyl, t-butylsulfanyl,cyclopropylsulfanyl, phenylsulfanyl, nitro, cyano, amino, dimethylamino,(cyclohexylmethyl)amino, acetyl, —SCF₃, iodo, fluoro, chloro, bromo,trifluoromethyl, —OCF₃, and methoxycarbonyl.
 13. The compound of claim 1wherein there is one R^(a).
 14. The compound of claim 1 wherein there isone R^(a) positioned on the ring para to the amide substituent.
 15. Thecompound of claim 1 wherein two adjacent R^(a) are taken together withthe carbons of attachment to form a fused phenyl ring.
 16. The compoundof claim 1 wherein there are two R^(a) substituents.
 17. The compound ofclaim 1 wherein each R^(a) is independently selected from the groupconsisting of methyl, i-propyl, ethenyl, 2-propenyl, cyclopropyl,phenyl, thiophenyl, methoxy, ethoxy, propoxy, i-propoxy, nitro, cyano,dimethylamino, (cyclohexylmethyl)amino, acetyl, fluoro, chloro, bromo,iodo, —CF₃, and fused phenyl.
 18. The compound of claim 1 wherein twoR^(b) are 2,6-difluoro or 2,4-difluoro.
 19. The compound of claim 1wherein two adjacent R^(b) substituents at 2- and 3-positions are takenwith the benzene ring of attachment to form benzothiazole,benzothiadiazole, or quinoxaline.
 20. The compound of claim 1 whereinR^(c) is selected from the group consisting of hydrogen, methyl, ethyl,i-propyl, hydroxymethyl, methoxymethyl, dimethylaminomethyl,methylsulfanylmethyl, methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl, methoxycarbonylmethyl, carboxy, carboxymethyl,carbamoyl, carbamoylmethyl, dimethylcarbamoyl, piperidine-1-carbonyl,5-methyl-2-oxo-[1,3]dioxol-4-yl-methoxycarbonyl,3-pyridylmethoxycarbonyl, 3-chlorobenzylcarbamoyl,4-fluorobenzylcarbamoyl, benzylcarbamoyl, phenylcarbamoyl,dimethylcarbamoylmethoxycarbonyl, and 2-morpholin-4-ylethoxycarbonyl.21. The compound of claim 1 wherein the carbon to which the two R^(c)groups are attached is in the (S) configuration.
 22. The compound ofclaim 1 wherein R^(d) is selected from the group consisting of hydrogen,methyl, ethyl, i-propyl, hydroxy, hydroxymethyl, methoxymethyl,dimethylaminomethyl, phenyl, 4-chlorophenyl, and methylsulfanylmethyl.23. The compound of claim 1 wherein two R^(d) together form ═O.
 24. Thecompound of claim 1 wherein R^(d) is selected from the group consistingof hydrogen, methyl, phenyl, and hydroxy.
 25. The compound of claim 1wherein said pharmaceutically acceptable salt is an amino addition salt.26. The compound of claim 1 wherein said pharmaceutically acceptablesalt is an acid addition salt.
 27. The compound of claim 1 wherein saidpharmaceutically acceptable salt is selected from the group consistingof hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,oxalate, valerate, oleate, palmitate, stearate, laurate, borate,benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactiobionate, and laurylsulfonate.
 28. The compound of claim 1 whereinsaid pharmaceutically acceptable salt is selected from the groupconsisting of sodium, potassium, calcium, magnesium, ammonium,quaternary ammonium, tetramethyl ammonium, methylammonium,trimethylammonium, and ethylammonium.
 29. The compound of claim 1selected from the group consisting of:(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2(4-chloro-phenyl)-propyl]-benzamide;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-enzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichlorobenzoylamino]-3-phenyl-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-phenyl)-propionicacid;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2,2-bis-(4-chloro-phenyl)-ethyl]-4-chloro-benzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(4-chloro-phenyl)-2-methyl-propyl]-benzamide;(S)-3-(5-Bromo-thiophen-2-yl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester;(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-naphthalen-2-yl-propionicacid;(±)-4-Chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-2-(2,4-difluorobenzenesulfonylamino)-benzamide;(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[1-carbamoyl-2-(4-chloro-phenyl)-ethyl]-4,5-dichloro-benzamide;(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-1-hydroxymethyl-ethyl]-4-methyl-benzamide;(S)-Benzo[1,2,5]thiadiazole-4-sulfonicacid[6-bromo-1,3-dioxo-2-(2-phenyl-propyl)-2,3-dihydro-1H-isoindol-4-yl]-amide;(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionicacid;(R)-3-(4-Chloro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid;(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-N-[2-3,4-dichloro-phenyl)-propyl]-benzamide;(R)-2-[2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-3-phenyl-propionicacid;(±)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(3,4-dichloro-phenyl)-3-oxo-propionicacid methyl ester;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionicacid;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-methyl-N-phenethyl-benzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-[2-4-chloro-phenyl)-propyl]-benzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-1-methyl-ethyl]-4-trifluoromethyl-benzamide;2-(Benzothiazole-4-sulfonylamino)-4-bromo-N-[2-(4-chloro-phenyl)-1-methyl-ethyl]-benzamide;4-Bromo-N-[2-(4-chloro-phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-benzamide;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-phenyl-propionicacid;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-trifluoromethyl-benzoylamino]-3-phenyl-propionicacid;2-[4-Iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-phenyl-propionicacid;2-[2-(Benzothiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-phenyl-propionicacid;2-[4,5-Dichloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-phenyl-propionicacid;4-Bromo-N-[2-(3,4-dichloro-phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-benzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-(2-phenyl-propyl)-benzamide;3-(3,4-Dichloro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-propionicacid;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-propionicacid;3-(4-Chloro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-propionicacid;(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-(2-phenyl-propyl)-benzamide;(R)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-(2-phenyl-propyl)-benzamide;(S)-4-Bromo-2-(2,6-difluoro-benzenesulfonylamino)-N-(2-phenyl-propyl)-benzamide;(R)-4-Bromo-2-(2,6-difluoro-benzenesulfonylamino)-N-(2-phenyl-propyl)-benzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(3,4-dichloro-phenyl)-propyl-4-iodo-benzamide;N-[2-(3,4-Dichloro-phenyl)-propyl]-4-iodo-2-(quinoxaline-5-sulfonylamino)-benzamide;2-[4-Bromo-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino-3-2,4-dichloro-phenyl)-propionicacid;N-[2-(3,4-Dichloro-phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzamide;4-Chloro-N-[2-(2,4-dichloro-phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-benzamide;4-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-N-[2-(4-nitro-phenyl)-propyl]-benzamide;4-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-N-[2-(4-trifluoromethyl-phenyl)-propyl]-benzamide;2-[4-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino]-3-(2,4-dichloro-phenyl)-propionicacid;N-[2-(2,4-Dichloro-phenyl)-propyl]-2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzamide;2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-N-[2-(4-nitro-phenyl)-propylenzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-((2S,1R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-benzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-indan-2-yl-benzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-methyl-N-(2-pyridin-2-yl-ethyl)-benzamidehydrochloride;(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(4-chloro-phenyl)-1-hydroxymethyl-ethyl]-benzamide;(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-[2-(4-chloro-phenyl)-1-methyl-ethyl]-benzamide;(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-propyl]-4-methyl-benzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[(1R,2S)-2-4-chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-benzamide;(2S,3R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-butyricacid;(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide;(±)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-N-[2-3,4-dichloro-phenyl)-propyl]-benzamide;(±)-4-Chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-2-quinoxaline-5-sulfonylamino)-benzamide;(R)-3-(3,4-Dichloro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid;(±)-N-[2-(3,4-Dichloro-phenyl)-propyl]-4-iodo-2-(quinoxaline-5-sulfonylamino)-benzamide;(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoylamino)-3-(4-chloro-phenyl)-propionicacid;(S)-2-[4-Chloro-2-(quinoxaline-6-sulfonylamino)benzoylamino]-3-(3-cyano-phenyl)-propionicacid;(S)-3-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-4-(3,4-dichloro-phenyl)-butyricacid;(S)-3-Benzo[b]thiophen-3-yl-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester;(S)-3-Benzo[b]thiophen-3-yl-2-[4-chloro-2-quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionicacid methyl ester;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionicacid;(R)-2-[4-Chloro-2-(2,4-difluoro-benzenesulfonylamino)-benzoylamino]-3-(4-chloro-phenyl)-propionicacid methyl ester;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(2,4-dichloro-phenyl)-ethyl]-benzamide;(S)-2-[4-Chloro-2-(2,4-difluoro-benzenesulfonylamino)-benzoylamino]-3-(4-chloro-phenyl)-propionicacid methyl ester;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-propyl]-4-iodo-benzamide;(R)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-2-hydroxy-1-methyl-2,2-diphenyl-ethyl)-benzamide;(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-2-hydroxy-1-methyl-2,2-diphenyl-ethyl)-benzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(2,4-dichloro-phenyl)-ethyl]-benzamide;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(4-fluoro-phenyl)-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-thiophen-3-yl-propionicacid;(S)-3-(3-Chloro-phenyl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid;(S)-2-[4-Iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-p-tolyl-propionicacid;N-[2-(4-Bromo-phenyl)-ethyl]-4-chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-6-chloro-N-[2-(3,4-dichloro-phenyl)-propyl]-benzamide;(R)-3-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-4-[3,4-dichloro-phenyl)-butyricacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoylamino]-3-(4-chloro-phenyl)-propionicacid; (S)-2-[4-Chloro2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(3-nitro-phenyl)-propionicacid;(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(3,4-difluoro-phenyl)-propionicacid;(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-3-(4-cyano-phenyl)-propionicacid;(S)-2-[4-Chloro-2-(quinoxaline-5-sulfonylamino)benzoylamino]-3-thiophen-3-yl-propionicacid;(S)-4-(4-Chloro-phenyl)-3-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-butyricacid methyl ester;(S)-4-(4-Chloro-phenyl)-3-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-butyricacid;(S)-3-(4-Chloro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-3-iodo-phenyl)-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3,3bis-(4-chloro-phenyl)-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyricacid;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-2-methyl-propionicacid;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-phenyl)-propionicacid;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-3-hydroxy-propionicacid;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[(2S,1R)-2-(4-chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(3,4-dichloro-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[(2S,1R)-2-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionicacid;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-phenyl)-butyricacid;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(3-bromo-phenyl)-propyl]-4-iodo-benzamide;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-acrylicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyricacid;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[(2S,1R)-2-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-4-chloro-benzamide;2-[2-(Benzooxazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionicacid;2-[2-(Benzooxazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichlorophenyl)-propionicacid;2-[2-(Benzo[1,3]dioxole-4-sulfonylamino)-4-iodo-enzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid;2-(Benzo[1,3]dioxole-4-sulfonylamino)-4-chloro-N-[2-(4-chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-benzamide;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino3-(3-bromo-4-fluoro-phenyl)-propionicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid pyridin-3-ylmethyl ester;(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-phenyl)-propionicacid;(2S,3R)-3-(3,4-Dichloro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-butyricacid methyl ester;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid;(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid;(S)-2-[4-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid;(R)-2-[4-Chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid;anti-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid methyl ester;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid methyl ester;(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester;(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-propionicacid methyl ester;(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid;(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-propionicacid;(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[1-(3-chloro-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethyl]-benzamide;(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[1-benzylcarbamoyl-2-(3,4-dichloro-phenyl)-ethyl]-4-chloro-benzamide;(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-3,4-dichloro-phenyl)-1-(4-fluoro-benzylcarbamoyl)-ethyl]-benzamide;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4sulfonylamino)-4-bromo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid;(S)-3-(3,4-Dichloro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(2,4-dichloro-phenyl)-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(2,4-dichloro-5-fluoro-phenyl)-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-iodo-phenyl)-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-3-iodo-phenyl)-propionicacid methyl ester;(S)-3-(4-Chloro-3-iodo-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester;(S)-3-(4-Chloro-3-iodo-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid;(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-3,4-dichloro-phenyl)-1-phenylcarbamoyl-ethyl]-benzamide;(S)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[1-(3,4-dichloro-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-benzamide;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid methyl ester;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid methyl ester;(Z)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3,4-dichloro-phenyl)-acrylicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid;(S)-3-(3-Bromo-4-chloro-phenyl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid;(S)-3-(3-Bromo-4-chloro-phenyl)-2-[4,5-dichloro-2-quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid methyl ester;(S)-2-42-(Benzo[1,2,5thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid methyl ester;(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-bromo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester;(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester;(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid methyl ester;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionicacid methyl ester;(S)-3-(3-Bromo-4-chloro-phenyl)-2-[4-bromo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid; (S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4chlorobenzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid;(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-bromo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid;(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionicacid;(S)-3-(3-Bromo-4-fluoro-phenyl)-2-[4,5-dichloro-2-(quinoxaline-6-sulfonylamino)-benzoylamino]-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-enzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichlorobenzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid ethyl ester;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionicacid;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-3-iodo-phenyl)-propionicacid;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid; 2-[2-(Benzo[1,2,5]thiadiazole-4sulfonylamino)-4-iodo-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionicacid;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyricacid;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(4-chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-4-iodo-benzamide;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl)-4-iodo-benzamide;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionicacid;2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyricacid;2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[2-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-4-chloro-benzamide;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid tert-butyl ester;(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid 2-morpholin-4-yl-ethyl ester; and(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionicacid dimethylcarbamoylmethyl ester.
 30. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and an effective amountof at least one compound of formula (I):

wherein X is C₁₋₂alkyl or a bond; R¹ is selected from the groupconsisting of a) naphthyl, phenyl, said phenyl optionally fused at twoadjacent carbon atoms to R^(f), R^(f) is a linear 3- to 5-memberedhydrocarbon moiety-having 0 or 1 unsaturated bonds and having 0, 1 or 2carbon members which is a carbonyl, b) Ar⁶—, where Ar⁶ is a 6-memberedheteroaryl having carbon as a point of attachment, having 1 or 2heteroatom members which are —N═ and optionally benzo or pyrido fused,c) Ar⁵—, where Ar⁵ is a 5-membered heteroaryl having carbon as a pointof attachment, having 1 heteroatom member selected from the groupconsisting of O, S, >NH, and >NC₁₋₄alkyl, having 0 or 1 additionalheteroatom member which is —N═ and optionally benzo or pyrido fused, d)Ar⁶⁻⁶—, where Ar⁶⁻⁶ is phenyl having the point of attachment and fusedto a 6-membered heteroaryl having 1 or 2 heteroatom members which are—N═, e) Ar⁶⁻⁵—, where Ar⁶⁻⁵ is phenyl or pyridyl having the point ofattachment and fused to a 5-membered heteroaryl having 1 heteroatommember selected from the group consisting of O, S, >NH, and >NC₁₋₄alkyl,and having 0 or 1 additional heteroatom member which is —N═, where eachof a) to e) is substituted with 0, 1, 2, or 3 of R^(q), R^(q) isindependently selected from the group consisting of —C₁₋₄alkyl, hydroxy,fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, cyano,aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl,HO—C₁₋₄alkyl, C₁₋₄alkylO—C₁₋₄alkyl, HS—C₁₋₄alkyl, C₁₋₄alkylS—C₁₋₄alkyl,C₁₋₄alkoxy, and C₁₋₄alkylS—; R² is selected from the group consisting of—H, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₇cycloalkyl, and—C₃₋₇cycloalkenyl; R^(a) is, independently, selected from the groupconsisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl,furanyl, thiophenyl, benzyl, pyrrol-1-yl, —OH, —OC₁₋₆alkyl,—OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl,—SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, cyano, nitro, —N(R^(y))R^(z)(wherein R^(y) and R^(z) are independently —H, —C₁₋₄alkyl, orC₁₋₆cycloalkylC₁₋₄alkyl), —(C═O)C₁₋₄alkyl, —SCF₃, halo, trifluoromethyl,—OCF₃, and —COOC₁₋₄alkyl, —COOH, or, alternatively, two adjacent R^(a),may be taken together with the carbons of attachment to form a fusedring selected from the group consisting of phenyl, pyridyl, andpyrimidinyl; alternatively, R² and one of R^(a) may be taken together as—CH₂— or >C═O to form a fused ring to the phenyl; R^(b) is selected fromthe group consisting of 2,4-difluoro, 2,6-difluoro, or alternatively,two adjacent R^(b) substituents at 2- and 3-positions may be takentogether to form a five- or six-membered heterocyclic ring selected fromthe group consisting of oxazole, thiazole, thiadiazole, [1,3]dioxole,and pyrazine; R^(c) is independently selected from the group-consistingof hydrogen, —C₁₋₄alkyl, perhaloC₁₋₄alkyl, mono- or di-haloC₁₋₄alkyl,aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl,HO—C₁₋₄alkyl, HS—C₁₋₄alkyl, C₁₋₄alkylS—C₁₋₄alkyl,—C₀₋₂alkylCOOC₁₋₄alkyl, —C₀₋₂alkylCOOH, and —C₀₋₂alkylCON(R^(s))R^(t);—COO—C₀₋₂alkyl-ringA, and —COO—C₁₋₂alkyl—CON(R^(s))R^(t); R^(s) andR^(t) are independently selected from the group consisting of —H,—C₁₋₄alkyl, C₁₋₆cycloalkylC₁₋₄alkyl, phenyl, phenyl substituted withhalo, benzyl, benzyl substituted with halo, or alternatively, R^(s) andR^(t) taken together with their nitrogen of attachment form pyrrolidine,piperidine, or morpholine; ringA is selected from the group consistingof i) a 6-membered heteroaryl having carbon as a point of attachment andhaving 1 or 2 heteroatom members which are —N═; ii) a 5-memberedheteroaryl having carbon as a point of attachment, having 1 heteroatommember selected from the group consisting of O, S, >NH, and >NC₁₋₄alkyl,and having 0 or 1 additional heteroatom member which is —N═; and iii) a5- or 6-membered non-aromatic heterocycle having a carbon or nitrogen asa point of attachment, having 1 or 2 heteroatoms selected from the groupconsisting of O, S, and N, having 0 or 1 double bonds, having 0 or 1carbon member replaced by a carbonyl, and optionally substituted with—C₁₋₄alkyl, —OH, or halo; R^(d) is independently selected from the groupconsisting of hydrogen, —C₁₋₄alkyl, —OH, —OC₁₋₆alkyl, HO—C₁₋₄alkyl,perhaloC₁₋₄alkyl, mono- or di-haloC₁₋₄alkyl, aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl, HS—C₁₋₄alkyl,C₁₋₄alkylS—C₁₋₄alkyl, and optionally substituted phenyl; or two R^(d)together can be ═O where at least one R^(c) is selected from the groupconsisting of —COOC₁₋₄alkyl, —COO-ringA, —COOH, —CON(R^(s))R^(t), and—COOC₁₋₂alkylCON(R^(s))R^(t); alternatively, one R^(c) and one R^(d) maybe taken together to form a double bond; and enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof.
 31. A method for the treatment or prevention of pain,drug dependence, anxiety, panic attack, schizophrenia, pancreaticdisorders, secretory disorders, gastrointestinal motility disorders,functional bowel disease, biliary colic, and cancer, eating disorders,reflux diseases, gastroduodenal ulcers, refluxesophagitis, pepticulcers, Barrett's esophagus, antral G cell hyperplasia, perniciousanaemia, and Zollinger-Ellison syndrome, in mammals comprising the stepof administering to a mammal suffering there from an effective amount ofat least one compound of formula (I):

wherein X is C₁₋₂alkyl or a bond; R¹ is selected from the groupconsisting of a) naphthyl, phenyl, said phenyl optionally fused at twoadjacent carbon atoms to R^(f), R^(f) is a linear 3- to 5-memberedhydrocarbon moiety having 0 or 1 unsaturated bonds and having 0, 1 or 2carbon members which is a carbonyl, b) Ar⁶—, where Ar⁶ is a 6-memberedheteroaryl having carbon as a point of attachment, having 1 or 2heteroatom members which are —N═ and optionally benzo or pyrido fused,c) Ar⁵—, where Ar⁵ is a 5-membered heteroaryl having carbon as a pointof attachment, having 1 heteroatom member selected from the groupconsisting of O, S, >NH, and >NC₁₋₄alkyl, having 0 or 1 additionalheteroatom member which is —N═ and optionally benzo or pyrido fused, d)Ar⁶⁻⁶—, where Ar⁶⁻⁶, is phenyl having the point of attachment and fusedto a 6-membered heteroaryl having 1 or 2 heteroatom members which are—N═, e) Ar⁶⁻⁵—, where Ar⁶⁻⁵ is phenyl or pyridyl having the point ofattachment and fused to a 5-membered heteroaryl having 1 heteroatommember selected from the group consisting of O, S, >NH, and >NC₁₋₄alkyl,and having 0 or 1 additional heteroatom member which is —N═, where eachof a) to e) is substituted with 0, 1, 2, or 3 of R^(q), R^(q) isindependently selected from the group consisting of —C₁₋₄alkyl, hydroxy,fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, cyano,aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl,HO—C₁₋₄alkyl, C₁₋₄alkylO—C₁₋₄alkyl, HS—C₁₋₄alkyl, C₁₋₄alkylS—C₁₋₄alkyl,C₁₋₄alkoxy, and C₁₋₄alkylS—; R² is selected from the group consisting of—H, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₇cycloalkyl, and—C₃₋₇cycloalkenyl; R^(a) is, independently, selected from the groupconsisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl,furanyl, thiophenyl, benzyl, pyrrol-1-yl, —OH, —OC₁₋₆alkyl,—OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl,—SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, cyano, nitro, —N(R^(y))R^(z)(wherein R^(y) and R^(z) are independently —H, —C₁₋₄alkyl, orC₁₋₆cycloalkylC₁₋₄alkyl), —(C═O)C₁₋₄alkyl, —SCF₃, halo, trifluoromethyl,—OCF₃, and —COOC₁₋₄alkyl, —COOH, or, alternatively, two adjacent R^(a),may be taken together with the carbons of attachment to form a fusedring selected from the group consisting of phenyl, pyridyl, andpyrimidinyl; alternatively, R² and one of R^(a) may be taken together as—CH₂— or >C═O to form a fused ring to the phenyl; R^(b) is selected fromthe group consisting of 2,4-difluoro, 2,6-difluoro, or alternatively,two adjacent R^(b) substituents at 2- and 3-positions may be takentogether to form a five- or six-membered heterocyclic ring selected fromthe group consisting of oxazole, thiazole, thiadiazole, [1,3]dioxole,and pyrazine; R^(c) is independently selected from the group consistingof hydrogen, —C₁₋₄alkyl, perhaloC₁₋₄alkyl, mono- or di-haloC₁ ₄alkyl,aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl,HO—C₁₋₄alkyl, HS—C₁₋₄alkyl, C₁₋₄alkylS—C₁₋₄alkyl,—C₀₋₂alkylCOOC₁₋₄alkyl, —C₀₋₂alkylCOOH, and —C₀₋₂alkyl-CON(R^(s))R^(t);—COO—C₀₋₂alkyl-ringA, and —COO—C₁₋₂alkyl—CON(R^(s))R^(t); R^(s) andR^(t) are independently selected from the group consisting of —H,—C₁₋₄alkyl, C₁₋₆cycloalkylC₁₋₄alkyl, phenyl, phenyl substituted withhalo, benzyl, benzyl substituted with halo, or alternatively, R^(s) andR^(t) taken together with their nitrogen of attachment form pyrrolidine,piperidine, or morpholine; ringA is selected from the group consistingof i) a 6-membered heteroaryl having carbon as a point of attachment andhaving 1 or 2 heteroatom members which are —N═; ii) a 5-memberedheteroaryl having carbon as a point of attachment, having 1 heteroatommember selected from the group consisting of O, S, >NH, and >NC₁₋₄alkyl,and having 0 or 1 additional heteroatom member which is —N═; and iii) a5- or 6-membered non-aromatic heterocycle having a carbon or nitrogen asa point of attachment, having 1 or 2 heteroatoms selected from thegroup-consisting of O, S, and N, having 0 or 1 double bonds, having 0 or1 carbon member replaced by a carbonyl, and optionally substituted with—C₁₋₄alkyl, —OH, or halo; R^(d) is independently selected from the groupconsisting of hydrogen, —C₁₋₄alkyl, —OH, —OC₁₋₆alkyl, HO—C₁₋₄alkyl,perhaloC₁₋₄alkyl, mono- or di-haloC₁₋₄alkyl, aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl, HS—C₁₋₄alkyl,C₁₋₄alkylS—C₁₋₄alkyl, and optionally substituted phenyl; or two R^(d)together can be ═O where at least one R^(c) is selected from the groupconsisting of —COOC₁₋₄alkyl, —COO-ringA, —COOH, —CON(R^(s))R^(t), and—COOC₁₋₂alkylCON(R^(s))R^(t); alternatively, one R^(c) and one R^(d) maybe taken together to form a double bond; and enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof.
 32. A method for the treatment or prevention ofpancreatic adenocarcinoma, pain, gastro-esophageal reflux disease,non-erosive reflux disease, anorexia, pancreatitis, gastroduodenalulcers, reflux esophagitis, anxiety, colon cancer, peptic ulcers,pancreatic tumors and gastric tumors in mammals comprising the step ofadministering to a mammal suffering there from an effective amount of atleast one compound of formula (I):

wherein X is C₁₋₂alkyl or a bond; R¹ is selected from the groupconsisting of a) naphthyl, phenyl, said phenyl optionally fused at twoadjacent carbon atoms to R^(f), R^(f) is a linear 3- to 5-memberedhydrocarbon moiety having 0 or 1 unsaturated bonds and having 0, 1 or 2carbon members which is a carbonyl, b) Ar⁶—, where Ar⁶ is a 6-memberedheteroaryl having carbon as a point of attachment, having 1 or 2heteroatom members which are —N═ and optionally benzo or pyrido fused,c) Ar⁵—, where Ar⁵ is a 5-membered heteroaryl having carbon as a pointof attachment, having 1 heteroatom member selected from the groupconsisting of O, S, >NH, and >NC₁₋₄alkyl, having 0 or 1 additionalheteroatom member which is —N═ and optionally benzo or pyrido fused, d)Ar⁶⁻⁶—, where Ar⁶⁻⁶ is phenyl having the point of attachment and fusedto a 6-membered heteroaryl having 1 or 2 heteroatom members which are—N═, e) Ar⁶⁻⁵—, where Ar⁶⁻⁵ is phenyl or pyridyl having the point ofattachment and fused to a 5-membered heteroaryl having 1 heteroatommember selected from the group consisting of O, S, >NH, and >NC₁₋₄alkyl,and having 0 or 1 additional heteroatom member which is —N═, where eachof a) to e) is substituted with 0, 1, 2, or 3 of R^(q), R^(q) isindependently selected from the group consisting of —C₁₋₄alkyl, hydroxy,fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, cyano,aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl,HO—C₁₋₄alkyl, C₁₋₄alkylO—C₁₋₄alkyl, HS—C₁₋₄alkyl, C₁₋₄alkylS—C₁₋₄alkyl,C₁₋₄alkoxy, and C₁₋₄alkylS—; R² is selected from the group consisting of—H, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₇cycloalkyl, and—C₃₋₇cycloalkenyl; R^(a) is, independently, selected from the groupconsisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl,furanyl, thiophenyl, benzyl, pyrrol-1-yl, —OH, —OC₁₋₆alkyl,—OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl,—SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, cyano, nitro, —N(R^(y))R^(z)(wherein R^(y) and R^(z) are independently —H, —C₁₋₄alkyl, orC₁₋₆cycloalkylC₁₋₄alkyl), —(C═O)C₁₋₄alkyl, —SCF₃, halo, trifluoromethyl,—OCF₃, and —COOC₁₋₄alkyl, —COOH, or, alternatively, two adjacent R^(a),may be taken together with the carbons of attachment to form a fusedring selected from the group consisting of phenyl, pyridyl, andpyrimidinyl; alternatively, R² and one of R^(a) may be taken together as—CH₂— or >C═O to form a fused ring to the phenyl; R^(b) is selected fromthe group consisting of 2,4-difluoro, 2,6-difluoro, or alternatively,two adjacent R^(b) substituents at 2- and 3-positions may be takentogether to form a five- or six-membered heterocyclic ring selected fromthe group consisting of oxazole, thiazole, thiadiazole, [1,3]dioxole,and pyrazine; R^(c) is independently selected from the group consistingof hydrogen, —C₁₋₄alkyl, perhaloC₁₋₄alkyl, mono- or di-haloC₁₋₄alkyl,aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl,HO—C₁₋₄alkyl, HS—C₁₋₄alkyl, C₁₋₄alkylS—C₁₋₄alkyl,—C₀₋₂alkylCOOC₁₋₄alkyl, —C₀₋₂alkylCOOH, and —C₀₋₂alkylCON(R^(s))R^(t);—COO—C₀₋₂alkyl-ringA, and —COO—C₁₋₂alkyl—CON(R^(s))R^(t); R^(s) andR^(t) are independently selected from the group consisting of —H,—C₁₋₄alkyl, C₁₋₆cycloalkylC₁₋₄alkyl, phenyl, phenyl substituted withhalo, benzyl, benzyl substituted with halo, or alternatively, R^(s) andR^(t) taken together with their nitrogen of attachment form pyrrolidine,piperidine, or morpholine; ringA is selected from the group consistingof i) a 6-membered heteroaryl having carbon as a point of attachment andhaving 1 or 2 heteroatom members which are —N═; ii) a 5-memberedheteroaryl having carbon as a point of attachment, having 1 heteroatommember selected from the group consisting of O, S, >NH, and >NC₁₋₄alkyl,and having 0 or 1 additional heteroatom member which is —N═; and iii) a5- or 6-membered non-aromatic heterocycle having a carbon or nitrogen asa point of attachment, having 1 or 2 heteroatoms selected from the groupconsisting of O, S, and N, having 0 or 1 double bonds, having 0 or 1carbon member replaced by a carbonyl, and optionally substituted with—C₁₋₄alkyl, —OH, or halo; R^(d) is independently selected from the groupconsisting of hydrogen, —C₁₋₄alkyl, —OH, —OC₁₋₆alkyl, HO—C₁₋₄alkyl,perhaloC₁₋₄alkyl, mono- or di-haloC₁₋₄alkyl, aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl, HS—C₁₋₄alkyl,C₁₋₄alkylS—C₁₋₄alkyl, and optionally substituted phenyl; or two R^(d)together can be ═O where at least one R^(c) is selected from the groupconsisting of —COOC₁₋₄alkyl, —COO-ringA, —COOH, —CON(R^(s))R^(t), and—COOC₁₋₂alkylCON(R^(s))R^(t); alternatively, one R^(c) and one R^(d) maybe taken together to form a double bond; and enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof.
 33. A method for the treatment or prevention ofpancreatitis, non-erosive reflux disease, or gastroesophageal refluxdisease in mammals comprising the step of administering to a mammalsuffering there from an effective amount of at least one compound offormula (I):

wherein X is C₁₋₂alkyl or a bond; R¹ is selected from the groupconsisting of a) naphthyl, phenyl, said phenyl optionally fused at twoadjacent carbon atoms to R^(f), R^(f) is a linear 3- to 5-memberedhydrocarbon moiety having 0 or 1 unsaturated bonds and having 0, 1 or 2carbon members which is a carbonyl, b) Ar⁶—, where Ar⁶ is a 6-memberedheteroaryl having carbon as a point of attachment, having 1 or 2heteroatom members which are —N═ and optionally benzo or pyrido fused,c) Ar⁵—, where Ar⁵ is a 5-membered heteroaryl having carbon as a pointof attachment, having 1 heteroatom member selected from the groupconsisting of O, S, >NH, and >NC₁₋₄alkyl, having 0 or 1 additionalheteroatom member which is —N═ and optionally benzo or pyrido fused, d)Ar⁶⁻⁶—, where Ar⁶⁻⁶ is phenyl having the point of attachment and fusedto a 6-membered heteroaryl having 1 or 2 heteroatom members which are—N═, e) Ar⁶⁻⁵—, where Ar⁶⁻⁵ is phenyl or pyridyl having the point ofattachment and fused to a 5-membered heteroaryl having 1 heteroatommember selected from the group consisting of O, S, >NH, and >NC₁₋₄alkyl,and having 0 or 1 additional heteroatom member which is —N═, where eachof a) to e) is substituted with 0, 1, 2, or 3 of R^(q), R^(q) isindependently selected from the group consisting of —C₁₋₄alkyl, hydroxy,fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, cyano,aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl,HO—C₁₋₄alkyl, C₁₋₄alkylO—C₁₋₄alkyl, HS—C₁₋₄alkyl, C₁₋₄alkylS—C₁₋₄alkyl,C₁₋₄alkoxy, and C₁₋₄alkylS—; R² is selected from the group consisting of—H, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₇cycloalkyl, and—C₃₋₇cycloalkenyl; R^(a) is, independently, selected from the groupconsisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl,furanyl, thiophenyl, benzyl, pyrrol-1-yl, —OH, —OC₁₋₆alkyl, —OCcycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl,—Sphenyl, —Sbenzyl, cyano, nitro, —N(R^(y))R^(z) (wherein R^(y) andR^(z) are independently —H, —C₁₋₄alkyl, or C₁₋₆cycloalkylC₁₋₄alkyl),—(C═O)C₁₋₄alkyl, —SCF₃, halo, trifluoromethyl, —OCF₃, and —COOC₁₋₄alkyl,—COOH, or, alternatively, two adjacent R^(a), may be taken together withthe carbons of attachment to form a fused ring selected from the groupconsisting of phenyl, pyridyl, and pyrimidinyl; alternatively, R² andone of R^(a) may be taken together as —CH₂— or >C═O to form a fused ringto the phenyl; R^(b) is selected from the group consisting of2,4-difluoro, 2,6-difluoro, or alternatively, two adjacent R^(b)substituents at 2- and 3-positions may be taken together to form a five-or six-membered heterocyclic ring selected from the group consisting ofoxazole, thiazole, thiadiazole, [1,3]dioxole, and pyrazine; R^(c) isindependently selected from the group consisting of hydrogen,—C₁₋₄alkyl, perhaloC₁₋₄alkyl, mono- or di-haloC₁₋₄alkyl, aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl, HO—C₁₋₄alkyl,HS—C₁₋₄alkyl, C₁₋₄alkylS—C₁₋₄alkyl, —C₀₋₂alkylCOOC₁₋₄alkyl,—C₀₋₂alkylCOOH, and —C₀₋₂alkylCON(R^(s))R^(t); —COO—C₀₋₂alkyl-ringA, and—COO—C₁₋₂alkyl—CON(R^(s))R^(t); R^(s) and R^(t) are independentlyselected from the group consisting of —H, —C₁₋₄alkyl,C₁₋₆cycloalkylC₁₋₄alkyl, phenyl, phenyl substituted with halo, benzyl,benzyl substituted with halo, or alternatively, R^(s) and R^(t) takentogether with their nitrogen of attachment form pyrrolidine, piperidine,or morpholine; ringA is selected from the group consisting of i) a6-membered heteroaryl having carbon as a point of attachment and having1 or 2 heteroatom members which are —N═; ii) a 5-membered heteroarylhaving carbon as a point of attachment, having 1 heteroatom memberselected from the group consisting of O, S, >NH, and >NC₁₋₄alkyl, andhaving 0 or 1 additional heteroatom member which is —N═; and iii) a 5-or 6-membered non-aromatic heterocycle having a carbon or nitrogen as apoint of attachment, having 1 or 2 heteroatoms selected from the groupconsisting of O, S, and N, having 0 or 1 double bonds, having 0 or 1carbon member replaced by a carbonyl, and optionally substituted with—C₁₋₄alkyl, —OH, or halo; R^(d) is independently selected from the groupconsisting of hydrogen, —C₁₋₄alkyl, —OH, —OC₁₋₆alkyl, HO—C₁₋₄alkyl,perhaloC₁₋₄alkyl, mono- or di-haloC₁₋₄alkyl, aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkyl, diC₁₋₄alkylaminoC₁₋₄alkyl, HS—C₁₋₄alkyl,C₁₋₄alkylS—C₁₋₄alkyl, and optionally substituted phenyl; or two R^(d)together can be ═O where at least one R^(c) is selected from the groupconsisting of —COOC₁₋₄alkyl, —COO-ringA, —COOH, —CON(R^(s))R^(t), and—COOC₁₋₂alkylCON(R^(s))R^(t); alternatively, one R^(c) and one R^(d) maybe taken together to form a double bond; and enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof.